5H-cyclopenta[d]pyrimidines as AKT protein kinase inhibitors

ABSTRACT

Compounds of Formula I are useful for inhibiting AKT protein kinases. Methods of using compounds of Formula I and stereoisomers and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

PRIORITY OF INVENTION

This application is a continuation of U.S. patent application Ser. No.12/812,377, which is a 35 U.S.C. 371 national stage application ofInternational Patent Application No. PCT/US2009/030617, filed Jan. 9,2009, and claims priority to U.S. Provisional Application No. 61/020,129that was filed on Jan. 9, 2008, which are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel inhibitors of serine/threonineprotein kinases (e.g., AKT and related kinases), to pharmaceuticalcompositions comprising the compounds, to a process for making thecompounds and to the use of the compounds in therapy. More particularlyit relates to certain 4-substituted 5H-cyclopenta[d]pyrimidines usefulin the treatment and prevention of hyperproliferative diseases, such ascancer and inflammation, in mammals.

2. Description of the State of the Art

Protein kinases (PK) are enzymes that catalyze the phosphorylation ofhydroxy groups on tyrosine, serine and threonine residues of proteins bytransfer of the terminal (gamma) phosphate from ATP. Through signaltransduction pathways, these enzymes modulate cell growth,differentiation and proliferation, i.e., virtually all aspects of celllife in one way or another depend on PK activity (Hardie, G. and Hanks,S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, SanDiego, Calif.). Furthermore, abnormal PK activity has been related to ahost of disorders, ranging from relatively non-life threatening diseasessuch as psoriasis to extremely virulent diseases such as glioblastoma(brain cancer). Protein kinases are an important target class fortherapeutic modulation (Cohen, P. (2002) Nature Rev. Drug Discovery1:309).

Significantly, atypical protein phosphorylation and/or expression isoften reported to be one of the causative effects of abnormal cellularproliferation, metastasis and cell survival in cancer. The abnormalregulation and/or expression of various kinases, including Akt, VEGF,ILK, ROCK, p70S6K, Bcl, PKA, PKC, Raf, Src, PDK1, ErbB2, MEK, IKK, Cdk,EGFR, BAD, CHK1, CHK2 and GSK3 amongst numerous others, has beenspecifically implicated in cancer.

Protein kinases include two classes; protein tyrosine kinases (PTK) andserine-threonine kinases (STK). The Protein Kinase B/Akt enzymes are agroup of serine/threonine kinases that are overexpressed in a variety ofhuman tumors. One of the best-characterized targets of the PI3K lipidproducts is the 57 KD serine/threonine protein kinase Akt, downstream ofPI3K in the signal transduction pathway (Hemmings, B. A. (1997) Science275:628; Hay N. (2005) Cancer Cell 8:179-183). Akt is the humanhomologue of the protooncogene v-akt of the acutely transformingretrovirus AKT8. Due to its high sequence homology to protein kinases Aand C, Akt is also called Protein Kinase B (PKB) and Related to A andC(RAC). Three isoforms of Akt are known to exist, namely Akt1, Akt2 andAkt3, which exhibit an overall homology of 80% (Staal, S. P. (1987)Proc. Natl. Acad. Sci. 84:5034; Nakatani, K. (1999) Biochem. Biophys.Res. Commun. 257:906; Li et al (2002) Current Topics in Med. Chem.2:939-971; WO 2005/113762). The Akt isoforms share a common domainorganization that consists of a pleckstrin homology domain at theN-terminus, a kinase catalytic domain, and a short regulatory region atthe C-terminus. In addition, both Akt2 and Akt3 exhibit splice variants.Upon recruitment to the cell membrane by PtdInd(3,4,5)P₃, Akt isphosphorylated (activated) by PDK1 at T308, T309 and T305 for isoformsAkt1 (PKBa), Akt2 (PKBβ) and Akt3 (PKBγ), respectively, and at S473,S474 and S472 for isoforms Akt1, Akt2 and Akt3, respectively. Suchphosphorylation is believed to occur by the mTOR-Rictor complex,although PDK1 (Balendran, A., (1999) Curr. Biol. 9:393),autophosphorylation (Toker, A. (2000) J. Biol. Chem. 275:8271) andintegrin-linked kinase (ILK) (Delcommenne, M. (1998) Proc. Natl. Acad.Sci. USA, 95:11211) have been implicated in this process. Akt activationrequires its phosphorylation on residue Ser 473 in the C-terminalhydrophobic motif (Brodbeck et al (1999) J. Biol. Chem. 274:9133-9136;Coffer et al (1991) Eur. J. Biochem. 201:475-481; Alessi et al (1997)Curr. Biol. 7:261-269). Although monophosphorylation of Akt activatesthe kinase, bis(phosphorylation) is required for maximal kinaseactivity.

Akt is believed to assert its effect on cancer by suppressing apoptosisand enhancing both angiogenesis and proliferation (Toker et al (2006)Cancer Res. 66(8):3963-3966). Akt is overexpressed in many forms ofhuman cancer including, but not limited to, colon (Zinda et al (2001)Clin. Cancer Res. 7:2475), ovarian (Cheng et al (1992) Proc. Natl. Acad.Sci. USA 89:9267), brain (Haas Kogan et al (1998) Curr. Biol. 8:1195),lung (Brognard et al (2001) Cancer Res. 61:3986), pancreatic (Bellacosaet al (1995) Int. J. Cancer 64:280-285; Cheng et al (1996) Proc. Natl.Acad. Sci. 93:3636-3641), prostate (Graff et al (2000) J. Biol. Chem.275:24500) and gastric carcinomas (Staal et al (1987) Proc. Natl. Acad.Sci. USA 84:5034-5037).

The PI3K/Akt/mammalian target of rapamycin (mTOR) pathway has beenexplored for targeted small molecule inhibitor therapy (Georgakis, G.and Younes, A. (2006) Expert Rev. Anticancer Ther. 6(1):131-140;Granville et al (2006) Clin. Cancer Res. 12(3):679-689). Inhibition ofPI3K/Akt signaling induces apoptosis and inhibits the growth of tumorcells that have elevated Akt levels (Kim et al (2005) Current Opinion inInvestig. Drugs 6(12):1250-1258; Luo et al (2005) Molecular Cancer Ther.4(6):977-986).

The development of kinase inhibitors that target abnormally regulatedpathways and ultimately result in disease is of enormous ethical andcommercial interest to the medical and pharmaceutical community. Acompound that inhibits (1) recruitment of Akt to the cell membrane, (2)activation by PDK1 or PDK2, (3) substrate phosphorylation, or (4) one ofthe downstream targets of Akt could be a valuable anticancer agent,either as a stand-alone therapy or in conjunction with other acceptedprocedures.

United States Patent Application Publication 2005/0130954 disclosesinter alia, a variety of compounds that act as AKT inhibitors. Thecompounds are said to be useful in the treatment of hyperproliferativediseases such as cancer.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to compounds that are inihibitorsof AKT protein kinases. Accordingly, the compounds of the invention areuseful in the treatment of hyperproliferative diseases, such as cancerand inflammation, in mammals.

More specifically, one aspect of the present invention providescompounds of Formula I:

and stereoisomers and pharmaceutically acceptable salts thereof, whereinR¹, R^(1a), R², R^(2a), L and A are as defined herein.

Another aspect of the present invention provides methods of preventingor treating a disease or disorder modulated by AKT, comprisingadministering to a mammal in need of such treatment an effective amountof a compound of this invention or a stereoisomer or pharmaceuticallyacceptable salt thereof. Examples of such diseases and disordersinclude, but are not limited to, hyperproliferative disorders (such ascancer), neurodegeneration, cardiac hypertrophy, pain, migraine andneurotraumatic disease.

Another aspect of the present invention provides methods of preventingor treating cancer, comprising administering to a mammal in need of suchtreatment an effective amount of a compound of this invention, or astereoisomer or pharmaceutically acceptable salt thereof, alone or incombination with one or more additional compounds having anti-cancerproperties.

In another aspect, the present invention provides a method of inhibitingthe production of AKT protein kinases in a mammal, which comprisesadministering to said mammal a compound of Formula I, or a stereoisomeror pharmaceutically acceptable salt thereof in an amount effective toinhibit production of an AKT protein kinase.

In still yet another aspect, the present invention provides methods ofinhibiting the activity of AKT protein kinases, comprising contactingsaid kinase with a compound of Formula I.

The inventive compounds may be used advantageously in combination withother known therapeutic agents. Accordingly, this invention alsoprovides pharmaceutical compositions comprising a compound of Formula Ior a stereoisomer or pharmaceutically acceptable salt thereof, incombination with a second therapeutic agent.

Another aspect of the present invention provides a method of treating ahyperproliferative disease in a mammal comprising administering atherapeutically effective amount of a compound of this invention to themammal.

Another aspect of the present invention provides the use of a compoundof this invention in the manufacture of a medicament for the treatmentof a hyperproliferative disease.

Another aspect of the present invention provides compounds of thepresent invention for use in the treatment of hyperproliferativediseases.

An additional aspect of the invention is the use of a compound ofFormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, for therapy. In one embodiment, the therapy comprises thetreatment of an AKT protein kinase-mediated condition.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention in thetreatment of a hyperproliferative disease.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention in thetreatment of cancer.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of this invention or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.

Another aspect of the present invention includes methods of preparing,methods of separation, and methods of purification of the compounds ofthis invention.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the present invention as defined by the claims. One skilled in theart will recognize many methods and materials similar or equivalent tothose described herein, which could be used in the practice of thepresent invention. The present invention is in no way limited to themethods and materials described. In the event that one or more of theincorporated literature and similar materials differs from orcontradicts this application, including but not limited to definedterms, term usage, described techniques, or the like, this applicationcontrols.

Definitions

The term “alkyl” includes linear or branched-chain radicals of carbonatoms. Some alkyl moieties have been abbreviated, for example, methyl(“Me”), ethyl (“Et”), propyl (“Pr”) and butyl (“Bu”), and furtherabbreviations are used to designate specific isomers of compounds, forexample, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”),1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”),1-methylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl(“t-Bu”) and the like. The abbreviations are sometimes used inconjunction with elemental abbreviations and chemical structures, forexample, methanol (“MeOH”) or ethanol (“EtOH”).

Additional abbreviations used throughout the application include, forexample, benzyl (“Bz”) and phenyl (“Ph”).

The terms “treat” or “treatment” refer to therapeutic, prophylactic,palliative or preventative measures. For purposes of this invention,beneficial or desired clinical results include, but are not limited to,alleviation of symptoms, diminishment of extent of disease, stabilized(i.e., not worsening) state of disease, delay or slowing of diseaseprogression, amelioration or palliation of the disease state, andremission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment. Those in need oftreatment include those already with the condition or disorder as wellas those prone to have the condition or disorder or those in which thecondition or disorder is to be prevented.

The phrases “therapeutically effective amount” or “effective amount”mean an amount of a compound of the present invention that, whenadministered to a mammal in need of such treatment, sufficient to (i)treat or prevent the particular disease, condition, or disorder, (ii)attenuate, ameliorate, or eliminate one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevent or delaythe onset of one or more symptoms of the particular disease, condition,or disorder described herein. The amount of a compound that willcorrespond to such an amount will vary depending upon factors such asthe particular compound, disease condition and its severity, theidentity (e.g., weight) of the mammal in need of treatment, but cannevertheless be routinely determined by one skilled in the art.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lungand squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer, colon cancer, rectal cancer, colorectal cancer, endometrial oruterine carcinoma, salivary gland carcinoma, kidney or renal cancer,prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, analcarcinoma, penile carcinoma, skin cancer, including melanoma, as well ashead and neck cancer.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention.

The compounds of this invention also include other salts of suchcompounds which are not necessarily pharmaceutically acceptable salts,and which may be useful as intermediates for preparing and/or purifyingcompounds of this invention and/or for separating enantiomers ofcompounds of this invention.

The term “mammal” means a warm-blooded animal that has or is at risk ofdeveloping a disease described herein and includes, but is not limitedto, guinea pigs, dogs, cats, rats, mice, hamsters, and primates,including humans.

AKT Inhibitors

The present invention provides compounds, and pharmaceuticalformulations thereof, that are potentially useful in the treatment ofdiseases, conditions and/or disorders modulated by AKT.

One embodiment of this invention provides compounds of Formula I:

and stereoisomers and pharmaceutically acceptable salts thereof,wherein:

R¹ and R^(1a) are independently selected from hydrogen, methyl, ethyl,—CH═CH₂, —CH₂OH, CF₃, CHF₂ or CH₂F;

R² is selected from hydrogen, OH, OCH₃ or F;

R^(2a) is selected from hydrogen, methyl or F, or

R² and R^(2a) are oxo;

L is selected from:

wherein the single wavy line is where L attaches to A and the doublewavy line is where L attaches to the pyrimidine;

A is:

X is a direct bond from L to Y, CH₂, O, C═O, NH or C(═O)NH;

Y is CH or N;

Z is absent, CH₂ or O, wherein L, X, Y, Z and b are selected so that anynitrogen is not bonded directly to another nitrogen;

G is phenyl optionally substituted with one to four R^(a) groups or a5-6 membered heteroaryl optionally substituted by a halogen;

R³ and R⁴ are independently selected from hydrogen or methyl;

R⁵ and R⁶ are independently selected from hydrogen or C₁-C₆ alkyl;

a is 0 or 1;

b is 0, 1 or 2; and

each R^(a) is independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,—O—(C₁-C₆-alkyl), CF₃, —OCF₃, S(C₁-C₆-alkyl), CN, —OCH₂-phenyl, NH₂,—NO₂, —NH—(C₁-C₆-alkyl), —N—(C₁-C₆-alkyl)₂, piperidine, pyrrolidine,CH₂F, CHF₂, —OCH₂F, —OCHF₂, —OH, —SO₂(C₁-C₆-alkyl), C(O)NH₂,C(O)NH(C₁-C₆-alkyl), and C(O)N(C₁-C₆-alkyl)₂; or

b is 1, R³ is hydrogen and R⁴ and R⁵ together with the atoms to whichthey are attached form an optionally substituted 5-6 memberedheterocyclic ring having one ring nitrogen atom, and R⁶ is selected fromthe group consisting of hydrogen or C₁-C₄ alkyl optionally substitutedwith OH or O(C₁-C₃ alkyl), such that A has the structure:

R^(c) and R^(d) are independently selected from hydrogen and methyl; and

c is 1 or 2; or

b is 1, Z is CH₂ and R⁵ and Y together with the atoms to which they areattached form an optionally substituted 6 membered heterocyclic ringhaving one ring nitrogen atom, and R⁶ is selected from the groupconsisting of hydrogen or C₁-C₄ alkyl optionally substituted with OH orO(C₁-C₃ alkyl), such that A has the structure:

In certain embodiments, R¹ is methyl.

In certain embodiments, R^(1a) is hydrogen.

In certain embodiments, R² is hydrogen.

In certain embodiments, R² is OH.

In certain embodiments, R^(2a) is hydrogen.

In certain embodiments, Formula I is selected from:

In certain embodiments, Formula I is selected from:

In certain embodiments, L is selected from:

In certain embodiments, L is:

wherein the single wavy line is where L attaches A and the double wavyline is where L attaches to the pyrimidine, providing compounds ofFormula Ia having the structure:

In certain embodiments, L is:

wherein the single wavy line is where L attaches A and the double wavyline is where L attaches to the pyrimidine, providing compounds ofFormula Ib having the structure:

In certain embodiments, L is:

wherein the single wavy line is where L attaches A and the double wavyline is where L attaches to the pyrimidine, providing compounds ofFormula Ic having the structure:

In certain embodiments, L is:

wherein the single wavy line is where L attaches A and the double wavyline is where L attaches to the pyrimidine, providing compounds ofFormula Id having the structure:

In certain embodiments, L is:

wherein the single wavy line is where L attaches A and the double wavyline is where L attaches to the pyrimidine, providing compounds ofFormula Ie having the structure:

In certain embodiments, L is:

wherein the single wavy line is where L attaches A and the double wavyline is where L attaches to the pyrimidine, providing compounds ofFormula If having the structure:

In certain embodiments, L is:

wherein the single wavy line is where L attaches A and the double wavyline is where L attaches to the pyrimidine, providing compounds ofFormula Ig having the structure:

In certain embodiments, L is:

wherein the single wavy line is where L attaches A and the double wavyline is where L attaches to the pyrimidine, providing compounds ofFormula Ih having the structure:

In certain embodiments, L is:

wherein the single wavy line is where L attaches A and the double wavyline is where L attaches to the pyrimidine, providing compounds ofFormula Ii having the structure:

In certain embodiments, A is:

In certain embodiments, X is a direct bond from L to Y, CH₂, O, C═O, NHor C(═O)NH.

In certain embodiments, X is a direct bond from L to Y.

In certain embodiments, X is CH₂.

In certain embodiments, X is O.

In certain embodiments, X is C═O.

In certain embodiments, X is NH.

In certain embodiments, X is C(═O)NH.

In certain embodiments, Y is CH or N.

In certain embodiments, Y is N.

In certain embodiments, Y is CH.

In certain embodiments, Z is absent, CH₂ or O.

In certain embodiments, Z is absent or O.

In certain embodiments, Z is absent.

In certain embodiments, Z is CH₂.

In certain embodiments, Z is O.

The compounds of Formula I are such that L, X, Y, Z and b are selectedso that any nitrogen is not bonded directly to another nitrogen.

In certain embodiments, X is a direct bond from L to Y, Y is CH₂ and Zis O, such that A has the structure A1:

In certain embodiments of A1, a is 0.

In certain embodiments of A1, b is 2.

In certain embodiments of A1, R³ is hydrogen.

In certain embodiments of A1, R⁴ is hydrogen.

In certain embodiments of A1, R⁵ is C₁-C₄ alkyl. In certain embodimentsof A1, R⁵ is methyl.

In certain embodiments of A1, R⁶ is C₁-C₄ alkyl. In certain embodimentsof A1, R⁶ is methyl.

In certain embodiments, X is C(═O)NH, Y is CH and Z is absent, such thatA has the structure A2:

In certain embodiments of A2, a is 1.

In certain embodiments of A2, b is 1.

In certain embodiments of A2, R³ is hydrogen.

In certain embodiments of A2, R⁴ is hydrogen.

In certain embodiments of A2, R⁵ is hydrogen.

In certain embodiments of A2, R⁶ is hydrogen.

In certain embodiments, X is a direct bond from L to Y, Y is CH and Z isabsent, such that A has the structure A3:

In certain embodiments of A3, a is 0.

In certain embodiments of A3, b is 1.

In certain embodiments of A3, R³ is hydrogen.

In certain embodiments of A3, R⁴ is hydrogen.

In certain embodiments of A3, R⁵ is C₁-C₄ alkyl. In certain embodimentsof A3, R⁵ is isopropyl.

In certain embodiments of A3, R⁶ is hydrogen.

In certain embodiments, X is a direct bond from L to Y, Y is CH and Z isabsent, such that A has the structure A4:

In certain embodiments of A4, a is 0.

In certain embodiments of A4, a is 1.

In certain embodiments of A4, b is 0.

In certain embodiments of A4, b is 1.

In certain embodiments of A4, R³ is hydrogen.

In certain embodiments of A4, R⁴ is hydrogen.

In certain embodiments of A4, R⁵ is hydrogen.

In certain embodiments of A4, R⁵ is C₁-C₄ alkyl. In certain embodimentsof A4, R⁵ is isopropyl.

In certain embodiments of A4, R⁶ is hydrogen.

In certain embodiments, X is NH, Y is CH and Z is absent, such that Ahas the structure A5:

In certain embodiments of A5, a is 0.

In certain embodiments of A5, b is 1.

In certain embodiments of A5, R³ is hydrogen.

In certain embodiments of A5, R⁴ is hydrogen.

In certain embodiments of A5, R⁵ is C₁-C₄ alkyl. In certain embodimentsof A5, R⁵ is isopropyl.

In certain embodiments of A5, R⁶ is hydrogen.

In certain embodiments, X is C═O, Y is N and Z is absent, such that Ahas the structure A6:

In the embodiments of A6, b must be 1 or 2.

In certain embodiments of A6, a is 1.

In certain embodiments of A6, b is 2.

In certain embodiments of A6, R³ is hydrogen.

In certain embodiments of A6, R⁴ is hydrogen.

In certain embodiments of A6, R⁵ is hydrogen.

In certain embodiments of A6, R⁶ is hydrogen.

In certain embodiments, X is C═O, Y is CH and Z is absent, such that Ahas the structure A7:

In certain embodiments of A7, a is 0.

In certain embodiments of A7, b is 1.

In certain embodiments of A7, R³ is hydrogen.

In certain embodiments of A7, R⁴ is hydrogen.

In certain embodiments of A7, R⁵ is C₁-C₄ alkyl. In certain embodimentsof A7, R⁵ is tert-butyl. In certain embodiments of A7, R⁵ is isopropyl.

In certain embodiments of A7, R⁶ is hydrogen.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R³ is methyl.

In certain embodiments, R⁴ is hydrogen.

In certain embodiments, R⁴ is methy.

In certain embodiments, R⁵ is hydrogen.

In certain embodiments, R⁵ is C₁-C₄ alkyl.

In certain embodiments, R⁵ is methyl.

In certain embodiments, R⁵ is isopropyl.

In certain embodiments, R⁵ is tert-butyl.

In certain embodiments, R⁶ is hydrogen.

In certain embodiments, R⁶ is methyl.

In certain embodiments, a is 1.

In certain embodiments, a is 0.

In certain embodiments, b is 0.

In certain embodiments, b is 1.

In certain embodiments, b is 2.

In certain embodiments, Z is O and b is 2.

In certain embodiments, b is 1, R³ is hydrogen and R⁴ and R⁵ togetherwith the atoms to which they are attached form an optionally substituted5-6 membered heterocyclic ring having one ring nitrogen atom, such thatA has the structure A8:

wherein c is 1 or 2, R^(c) and R^(d) are independently selected fromhydrogen and methyl, and R⁶ is selected from the group consisting of Hor C₁-C₄ alkyl optionally substituted with OH or O(C₁-C₃ alkyl).

In certain embodiments, c is 1, such that A has the structure A8a:

In certain embodiments of A8a, X is C═O.

In certain embodiments of A8a, Y is CH.

In certain embodiments of A8a, Z is absent.

In certain embodiments of A8a, a is 0.

In certain embodiments of A8a, R^(c) is methyl.

In certain embodiments of A8a, R^(d) is methyl.

In certain embodiments of A8a, R⁶ is hydrogen.

In certain embodiments, c is 2, such that A has the structure A8b:

In certain embodiments, b is 1, Z is CH₂ and R⁵ and Y together with theatoms to which they are attached form an optionally substituted 6membered heterocyclic ring having one ring nitrogen atom, and R⁶ isselected from the group consisting of hydrogen or C₁-C₄ alkyl optionallysubstituted with OH or O(C₁-C₃ alkyl), such that A has the structure A9:

In certain embodiments of Formula A9, X is a direct bond from L to Y.

In certain embodiments of Formula A9, a is 0.

In certain embodiments of Formula A9, R⁶ is hydrogen.

In certain embodiments, G is phenyl optionally substituted with one tofour R^(a) groups or a 5-6 membered heteroaryl optionally substituted bya halogen.

In certain embodiments, each R^(a) is independently halogen,C₁-C₆-alkyl, C₃-C₆-cycloalkyl, —O—(C₁-C₆-alkyl), CF₃, —OCF₃,S(C₁-C₆-alkyl), CN, —OCH₂-phenyl, NH₂, —NO₂, —NH—(C₁-C₆-alkyl),—N—(C₁-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂, —OCH₂F, —OCHF₂,—OH, —SO₂(C₁-C₆-alkyl), C(O)NH₂, C(O)NH(C₁-C₆-alkyl), andC(O)N(C₁-C₆-alkyl)₂.

Referring to the G group of Formula I, examples include phenyloptionally substituted with one or more R^(a) groups independentlyselected from F, Cl, Br, I, methyl, ethyl, isopropyl, tert-butyl,cyclopropyl, CN, CF₃, —OMe, —OEt, —OCF₃, —NO₂, —SMe and —OCH₂Ph.Exemplary embodiments of G include phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl,4-trifluoromethylphenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-ethoxyphenyl,4-thiomethylphenyl, 4-trifluoromethoxyphenyl, 4-cyclopropylphenyl,4-chloro-3-fluorophenyl, 3,4-difluorophenyl, 4-bromo-3-fluorophenyl,3-fluoro-4-methylphenyl, 3-fluoro-4-methoxyphenyl,3-fluoro-4-trifluoromethylphenyl, 4-cyano-3-fluorophenyl,3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 3,5-dichlorophenyl.3,5-difluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl,3-bromo-4-fluorophenyl, 3,5-difluoro-4-chlorophenyl,2,3-difluoro-4-chlorophenyl, 2,5-difluoro-4-chlorophenyl,3,5-difluoro-4-bromophenyl, 2,3-difluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 4-(OCH₂Ph)-phenyl, 4-chlorophenyl,2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-bromophenyl, 4-fluorophenyl,3,4-difluorophenyl, 2,4-difluorophenyl 4-bromophenyl,4-chloro-2-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl,4-trifluoromethylphenyl, 4-iodophenyl, 4-nitrophenyl,4-tert-butylphenyl, 2-fluorophenyl, 3-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-trifluoromethoxyphenyl,3-fluoro-4-trifluoromethylphenyl and 4-trifluoromethoxyphenyl.

In certain embodiments, G is 4-chlorophenyl, 4-bromophenyl,4-trifluoromethylphenyl or 2,4-dichlorophenyl.

Referring to the G group of Formula I, the phrase “5-6 memberedheteroaryl optionally substituted by a halogen” includes thiophenes andpyridines, optionally substituted by halogens. Particular examplesinclude, but are not limited to, the structures:

It will be appreciated that certain compounds of the invention maycontain asymmetric or chiral centers, and therefore exist in differentstereoisomeric forms. It is intended that all stereoisomeric forms ofthe compounds of the invention, including but not limited to,diastereomers, enantiomers and atropisomers, as well as mixtures thereofsuch as racemic mixtures, form part of the present invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

It will be further appreciated that the compounds of the presentinvention may exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike, and it is intended that the invention embrace both solvated andunsolvated forms.

Synthesis of Compounds

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Sigma-Aldrich (St. Louis, Mo.), Alfa Aesar (Ward Hill,Mass.), or TCI (Portland, Oreg.), or are readily prepared using methodswell known to those skilled in the art (e.g., prepared by methodsgenerally described in Louis F. Fieser and Mary Fieser, Reagents forOrganic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), or BeilsteinsHandbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin,including supplements (also available via the Beilstein onlinedatabase)).

For illustrative purposes, Schemes 1-20 shows a general method forpreparing the compounds of the present invention as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used to synthesizethe inventive compounds. Although specific starting materials andreagents are depicted in the Schemes and discussed below, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme 1 shows a method of preparing compounds 7, wherein Hal is Br, Clor I. According to Scheme 1, intermediate 3 can be prepared bybrominating (+)-pulegone 1 to provide the di-bromide 2. The di-bromide 2is then treated with a base, such as sodium ethoxide. Oxidative cleavage(e.g., ozonolysis at −80° C. to −50° C.) of the pulegenate 3, whereinR^(f) is C₁-C₃ alkyl, gives the ketoester 4. The pyrimidine ring 5 isconstructed by reaction of the ketoester 4 with thiourea in the presenceof a base, such as KOH. The mercapto group at the 2-position of compound5 is eliminated by reduction (e.g., Raney Ni in ammonia) to givecompound 6. Alternatively, the ketoester 4 can be converted to the samehydroxypyrimidine 6 by treatment with, for example, an ammonia synthon,such as NH₄OAc, followed by treatment with NH₄CO₂H in the presence offormamide at 50° C. to 250° C. and/or at high pressure. Activation ofthe hydroxypyrimidine 6 (e.g., POCl₃) provides the 4-halopyrimidine 7.

Scheme 2 shows a method of preparing compound 11, wherein Hal is Br, Clor I and R¹ and R^(1a) are defined herein. According to Scheme 2,amination of compound 8, wherein R^(g) is C₁-C₃ alkyl, using an ammoniasynthon (e.g., NH₄OAc) gives compound 9. Pyrimidine formation using, forexample, ammonium formate in the presence of formamide at 50° C. to 250°C. and/or at high pressure gives the bicyclic unit 10. Activation ofcompound 10 using, for example, POCl₃ or SOCl₂ gives the activatedpyrimidine 11.

Scheme 3 shows an alternative method of preparing compound 11, whereinHal is Br, Cl or I and R¹ and R^(1a) groups are defined herein.According to Scheme 3, the pyrimidine ring is constructed by reactingthe ketoester 8, wherein R^(g) is C₁-C₃ alkyl, with thiourea in thepresence of a base, such as KOH. The mercapto group at 2-position ofcompound 12 is eliminated by reduction (e.g., Raney Ni in ammonia) togive 10. Activation of compound 10 using, for example, POCl₃ or SOCl₂gives the activated pyrimidine 11.

Scheme 4 shows a method of preparing compounds 16, 17, 18 and 19,wherein Hal is Br, Cl or I and R¹ and R^(1a) are defined herein.According to Scheme 4, oxidation of the 4-halopyrimidine 11 with anoxidizing agent, such as m-chloroperbenzoic acid (“m-CPBA”), Oxone orhydrogen peroxide provides the N-oxide 13. Rearrangement of the N-oxide13 with acetic anhydride yields the intermediate 14, wherein R^(j) ismethyl if acetic anhydride is used. Compound 14 is then hydrolyzed undermild conditions (e.g., LiOH in an aqueous/organic solvent mixture at 0°C. to room temperature) to give the alcohol 15. Compound 15 is theneither: 1) subjected to separation (e.g., chromatography with a chiralor achiral stationary phase); 2) functionalized (e.g., 4-nitrobenzoylchloride, NEt₃) to facilitate separation, separated (e.g.,chromatography or recrystallisation) and then hydrolyzed upon treatmentwith a base, such as lithium hydroxide, in an aqueous/organic solventmixture at 0° C. to room temperature; or 3) oxidized (e.g., Swernoxidation) followed by an asymmetric reduction (for example, a catalyticchiral catalyst in the presence of hydrogen, the Corey-Bakshi-Shibatacatalyst (“CBS catalyst”) or a borohydride reducing agent in thepresence of a chiral ligand). All alternatives provide a route into theseparate diastereomers 16 and 17.

Optionally, the 7-hydroxy group of compounds 16 and 17 may be alkylatedwith an alkylating reagent, such as an alkyl halide (e.g., MeI), in thepresence of a base, such as NaH or KOH, to provide compounds 18 and 19.

Scheme 5 shows a method of preparing compounds 20 and 21, wherein R^(k)is halogen or NO₂, Hal is Br, Cl or I and R¹ and R^(1a) are definedherein. According to Scheme 5, oxidation of the 4-haloopyrimidine 11with an oxidizing agent, such as m-CPBA, Oxone or hydrogen peroxide,provides the N-oxide 13. Rearrangement of the N-oxide 13 with aceticanhydride yields the intermediate 14, wherein R^(j) is methyl if aceticanhydride is used. Compound 14 is then hydrolyzed under mild conditions(e.g., LiOH in an aqueous/organic solvent mixture at 0° C. to roomtemperature) to give the alcohol 15. Compound 15 is then functionalized(e.g., 4-nitrobenzoyl chloride or 4-bromobenzoyl chloride in thepresence of NEt₃ at −20° C. to 50° C.) and separated (e.g.,chromatography or recrystallization) to provide a route into theseparate, protected diastereomers 20 and 21.

Scheme 6 shows a method for the formation of compounds 26 and 28,wherein R¹, R^(1a), R² and R^(2a) are as defined herein. A Pd-mediatedcoupling between the halopyrimidine 22, wherein Hal is Br, Cl or I andR^(k) is halogen or NO₂, and an appropriately substituted boronic acidor ester 23, wherein PG is an amine protecting group and R^(m) ishydrogen or alkyl optionally substituted with OH or the two R^(m) groupstogether with the atoms to which they are attached form a 5 or 6membered ring having one B atom and two O atoms with the remaindercarbon atoms, and the ring may be optionally substituted with alkylgroups, using, for example, Pd(PPh₃)₄ or Pd(dppf)Cl₂ in the presence ofNa₂CO₃ followed by removal of the benzoate protecting group (e.g., LiOHin an aqueous/organic solvent mixture at 0° C. to 50° C.) gives compound24. Removal of the amine protecting group (eg. for a Boc group,HCl/dioxane or TFA) and subsequent acylation (eg. HBTU, Hunig's base)gives 25.

Alternatively, optional reduction of the olefin 24 (e.g., H₂—Pd/C),followed by the removal of the amine protecting group (e.g., for a Bocgroup, HCl/dioxane or TFA) and subsequent acylation (e.g., HBTU, Hunig'sbase) gives 27.

Optional functionalization of the hydroxyl group of compounds 25 or 27may provide an entry into alternate R² groups. For example, the alcoholmay be converted to a fluoro group, wherein compounds 26 or 28 have R²as F and R^(2a) as H, by treatment with, for example, DAST.Alternatively, the alcohol of 25 or 27 may be alkylated (e.g., MeI, NaH)to give the methoxy analog, wherein compounds 26 or 28 have R² as OMeand R^(2a) as H. Alternatively, compounds 25 or 27 may be oxidized(e.g., Swern-like conditions) to provide the ketone, wherein compounds26 or 28 have R² and R^(2a) as oxo, which in turn could be treated witha fluorinating agent, such as DAST or Deoxo-Fluor, in an appropriatesolvent, such as dichloromethane (“DCM”) or chloroform, to give thegem-difluoride analogue, wherein compounds 26 or 28 have R² as F andR^(2a) as F.

Scheme 7 shows an alternative way to prepare compounds 26 and 28,wherein R¹, R^(1a), R² and R^(2a) are as defined herein. In this scheme,the pyrimidine moieties are functionalized at an earlier stage. APd-mediated coupling between the halopyrimidine 29, wherein Hal is Br,Cl or I, and an appropriately substituted boronic acid or ester 23,wherein PG is an amine protecting group and R^(m) is hydrogen or alkyloptionally substituted with OH or the two R^(m) groups together with theatoms to which they are attached form a 5 or 6 membered ring having oneB atom and two O atoms with the remainder carbon atoms, and the ring maybe optionally substituted with alkyl groups, using, for example,Pd(PPh₃)₄ or Pd(dppf)Cl₂ in the presence of Na₂CO₃, followed by theremoval of the benzoate protecting group (e.g., LiOH in anaqueous/organic solvent mixture at 0° C. to 50° C.) gives compound 30.Removal of the amine protecting group (e.g., for a Boc group,HCl/dioxane or TFA) and subsequent acylation (e.g., HBTU, Hunig's base)gives 26.

Alternatively, optional reduction of the olefin 30 (e.g., H₂—Pd/C),followed by the removal of the amine protecting group (e.g., for a Bocgroup, HCl/dioxane or TFA) and subsequent acylation (e.g., HBTU, Hunig'sbase) gives compound 28.

Scheme 8 shows a method of generating compounds 39 and 40, wherein R¹,R^(1a), R², R^(2a), R⁵ and G are as defined herein. An appropriatelysubstituted halobenzene 34, wherein Hal is Br, Cl or I, is treated witha strong base, such as BuLi, t-BuLi, Mg, etc., and addition of the newlyformed anion into the ketone of compound 33, wherein Pg is an amineprotecting group, at −100° C. to 50° C. gives compound 35. Compound 35is treated with a halobenzene 36, wherein Hal is Br, Cl or I, in thepresence of a Lewis acid (e.g., AlCl₃ at −20° C. to 100° C.) andreprotection of the amine, if necessary (e.g., Boc₂O for a Boc-group),gives compound 37. Conversion of compound 37 to an appropriateorganometallic (e.g., treatment with Sn₂Me₆, Pd(PPh₃)₄; bispinacol esterboronate, Pd(dppf)Cl₂; or Mg) followed by a Pd-mediated coupling withcompound 38, wherein R^(k) is halogen or NO₂, using, for example,PdCl₂(PPh₃)₂ and aqueous Na₂CO₃ in dioxane at room temperature toreflux, and final removal of the amine (e.g., HCl/dioxane for aBoc-group) and the alcohol protecting groups (e.g., LiOH in THF/H₂O at0° C. to 50° C.) gives compound 39.

Alternatively, a differentially functionalized pyrimidine moiety (e.g.,compound 29, wherein Hal is Br, Cl or I) could be used in the samePd-coupling and deprotection steps to give compound 40.

Scheme 9 shows a method of preparing compound 43. A palladium-mediatedcoupling between compound 38, wherein R^(k) is halogen or NO₂, andcompound 41 using, for example, PdCl₂(dppf) and aqueous Na₂CO₃ indioxane at room temperature to reflux, followed by saponification of theesters (e.g., LiOH or NaOH in THF/water at 0° C. to reflux) givescompound 42. The newly formed acid is treated with an appropriatelysubstituted primary or secondary amine under standard couplingconditions (e.g., HBTU/DIPEA/DMF) to give compound 43.

Scheme 10 shows a means of preparing compound 45, wherein R¹, R^(1a), R²and R^(2a) are as defined herein, with a differently substitutedpyrimidine moiety. A palladium-mediated coupling between compound 29,wherein Hal is Br, Cl or I, and compound 41 using, for example,PdCl₂(dppf) and aqueous Na₂CO₃ in dioxane at room temperature to reflux,followed by saponification of the ester (e.g., LiOH or NaOH in THF/waterat 0° C. to reflux) gives compound 44. Treatment of the newly formedacid with an appropriately substituted primary or secondary amine understandard coupling conditions (e.g., HBTU/DIPEA/DMF) gives compound 45.

Scheme 11 shows a means of generating compounds 48 and 50, wherein R¹,R^(1a), R² and R^(2a) are as defined herein. An appropriatelymono-substituted diazepine 46, wherein PG is an amine protecting group,is treated with compound 29, wherein Hal is Br, Cl or I, and a tertiaryamine base (e.g., Hunig's base) in a suitable solvent (e.g.,isopropanol) at room temperature to reflux, followed by removal of theamine protecting group, using, for example, in the case of a Boc-group,TFA or HCl/dioxane at 0° C. to room temperature to give compound 47.Treatment of compound 47 with an appropriately substituted acid usingstandard amide forming conditions (e.g., HBTU/DIPEA/DCM at 0° C. toreflux) gives compound 48.

Alternatively, an appropriately mono-substituted diazepine 46 is treatedwith compound 38, wherein R^(k) is halogen or NO₂, and a tertiary aminebase (e.g., Hunig's base) in a suitable solvent (e.g., isopropanol) atroom temperature to reflux, followed by removal of the amine protectinggroup, using, for example, in the case of a Boc-group, TFA orHCl/dioxane at 0° C. to room temperature to give compound 49. Compound49 is treated with an appropriately substituted acid using standardamide forming conditions (e.g., HBTU/DIPEA/DCM at 0° C. to reflux)followed by saponification of the ester (e.g., LiOH or NaOH in THF/waterat 0° C. to reflux) gives compound 50.

Scheme 12 shows a method for the formation of compounds 53 and 54,wherein R¹, R^(1a), R², R^(2a), R³, R⁴, R⁵, R⁶, G, a and b are asdefined herein. Compound 51, wherein PG is an amine protecting group, isreduced using, for example, NaBH₄ in EtOH at 0° C. to 50° C. Theresulting alcohol is then alkylated with an appropriate amine-containingside chain (e.g., N(CH₃)₂CH₂CH₂Cl) using, for example, a base such asNaH in DMF at room temperature to 100° C. This is followed bydeprotection of the piperidine amine using, for example, in the case ofBoc, HCl/dioxane or TFA at 0° C. to room temperature, gives compound 52.Compound 52 may then be treated with the halopyrimidine 29, wherein Halis Br, Cl or I, and a tertiary amine base (e.g., Hunig's base) in, forexample, DMF at room temperature to 140° C. to give compound 53.

Alternatively, compound 52 may be treated with compound 38, wherein Halis Br, Cl or I and R^(k) is halogen or NO₂, under similar conditions,followed by saponification of the benzoyl group using, for example, LiOHin THF/water at 0° C. to reflux to give compound 54.

Scheme 13 describes a route to prepare compound 61, wherein G and a areas defined herein. The amino acid 55 is reduced using, for example,LiBH₄ and ClSi(CH₃)₃ in THF at 0° C. to room temperature, followed byprotection of the amine, for example, using Boc₂O, if Pg is Boc, to givecompound 56, wherein PG is an amine protecting group. Activation of thealcohol 56 using, for example, methanesulphonyl chloride andtriethylamine in DCM at −20° C. to room temperature, followed bydisplacement with a protected amine, such as azide (using, for example,sodium azide in DMF at room temperature to 120° C.) and deprotection ofthe amine (for example, using HCl/dioxane or TFA for a Boc group) cangive the aminoazide 57. Compound 60 may be prepared by a palladiummediated coupling between the organozinc 59 and the chloropyrimidine 58using, for example, Pd(PPh₃)₄ in THF at room temperature to reflux,followed by saponification of the ester to give the acid 60. Coupling ofthe acid 60 and the amine 57 under standard conditions (e.g.,HBTU/Hunig's base) and reduction of the azide (e.g., H₂—Pd/C or PPh₃)can give compound 61.

Alternatively, instead of the chloropyrimidine 58, an alternativelysubstituted pyrimidine 29, wherein Hal is Br, Cl or I and R¹, R^(1a), R²and R^(2a) are as defined herein, may be used using similar proceduresto above, followed by saponification, to give compound 62. A similarcoupling with the amine 57 and azide reduction then gives compound 63.

Scheme 14 describes a method for the formation of compounds 67 and 68,wherein G and a are as defined herein. In this example, compounds 58 and59 are coupled using Pd-mediated conditions as described in Scheme 13.Following this, the pyrimidine-1-oxide is formed, using, for example,m-CPBA or Oxone, followed by acylation and rearrangement with aceticanhydride at higher temperature (e.g., 50° C. to reflux) and subsequentsaponification of the acetate and ester using, for example, LiOH inTHF/water at 0° C. to 50° C., to give the acid 64. Protection of theacid (e.g., MeOH, trimethylsilyldiazomethane at −20° C. to roomtemperature) as the methyl ester, followed by acylation of the alcohol(e.g., p-nitrobenzoyl chloride, NEt₃ in DCM at −20° C. to reflux) tofacilitate separation, separation (e.g. chromatography orrecrystallization) and saponification of the benzoate and methyl esters(using, for example, LiOH in THF/water at 0° C. to 50° C.) gives bothcompounds 65 and 66. These may be coupled with the aminoazide 57 usingstandard amide forming conditions (e.g., HBTU, Hunig's base, DCM at −20°C. to reflux), followed by reduction of the azide (e.g., H₂—Pd/C orPPh₃) to give compounds 67 and 68.

Optionally substituted forms of compounds 67 and 68 may be prepared byreplacing the chloropyrimidine 58 in Scheme 14, with the optionallysubstituted halopyrimidine 11, or by performing the transformationsdescribed in Scheme 17.

Scheme 15 describes the preparation of compounds 73, wherein R¹, R^(1a),R², R^(2a), R⁵, R⁶, G and a are as defined herein. A Pd-mediatedreaction between the halopyrimidine 29, wherein Hal is Br, Cl or I, andthe boronic acid 69 using, for example, PdCl₂(PPh₃)₂ and aqueous Na₂CO₃in isopropanol at room temperature to reflux, gives the phenol 70.Compound 72 is prepared by the amine-mediated opening of epoxide 71,followed by amine protection (e.g., Boc₂O) if the resulting amine isprimary or secondary. Coupling of compound 72 to compound 70 under, forexample, Mitsunobu conditions (e.g., diethylazodicarboxylate and PPh₃ at−40° to 5° C., followed by warming to temperatures up to 50° C.) andoptional deprotection, if required (e.g., HCl/dioxane or TFA for aBoc-group), gives compound 73.

Scheme 16 describes the preparation of compounds 77, wherein R¹, R^(1a),R², R^(2a), R⁵, R⁶ and G are as defined herein. The aniline 74 istreated with TMS-CN and an aldehyde in the presence of an acid, such assulphamic acid, in a protic solvent, such as MeOH, at 0° C. to 50° C.,followed by reduction of the resulting nitrile, using, for example,LiAlH₄ at −78° C. to room temperature in THF, gives compound 75.Alkylation of the amine (e.g., alkyl halide and base, such as NaH) orreductive amination using a suitable aldehyde or ketone in the presenceof a reducing agent, such as sodium triacetoxyborohydride, at 0° C. to50° C. gives compound 76. Compound 76 may then be converted to anappropriate organometallic reagent by treatment with, for example, aborane, PdCl₂(dppf) and KOAc in DMSO, Sn₂(CH₃)₆ and Pd(PPh₃)₄ oralternatively an activated form of Mg or Zn. This organometallic reagentmay then be coupled to the halopyrimidine 29, wherein Hal is Br, Cl orI, using a palladium-mediated reaction (e.g., Pd(PPh₃)₄ and aqueousNa₂CO₃ in, for example, isopropanol at room temperature to reflux) givescompound 77.

Scheme 17 shows a general method for the functionalization of thehydroxyl group of compound 79, wherein A, L, R¹ and R^(1a) are asdefined herein, providing alternative R² and R^(2a) groups. The alcohol79 may be converted to a fluoro-group 78 by treatment with afluorinating agent such as, for example, DAST. Alternatively, thealcohol 79 may be alkylated (e.g., a methylating agent such as MeI and astrong base, such as NaI) to give the methoxy analog 80 (in thisinstance, R^(2a) is hydrogen). Alternatively, compound 79 may beoxidized (e.g., Swern-like conditions) to provide the ketone 82, whichin turn could be treated with a fluorinating agent, such as DAST orDeoxo-Fluor, in an appropriate solvent, such as DCM or chloroform, togive the gem-difluoro analogue 81. Ketone 82 could also be treated withan appropriate organometallic nucleophile, such as MeMgBr or MeLi, togenerate the tertiary alcohol 83. This may be further fluorinated ormethylated as described above to give compounds 84 and 80 (in thisinstance, R^(2a) is methyl), respectively. Scheme 17 will generallyapply to compounds of Formula I and intermediates thereof, wherein R² isOH and R^(2a) is hydrogen.

Scheme 18 describes a process for preparing compound 88, wherein R¹,R^(1a), R², R^(2a), R³, R⁴, R⁵, R⁶, G, Z, a, and b are as definedherein. The acid 85 is converted to the hydrazide by treatment with, forexample, hydrazine under standard amide coupling conditions (e.g.,1,1-carbonyldiimidazole), followed by condensation with compound 86,wherein PG is an amine protecting group, at room temperature to 150° C.and removal of the protecting group (e.g., if Pg is Boc, the use ofHCl/dioxane or TFA) to give compound 87. Compound 87 is treated withcompound 29, wherein Hal is Br, Cl or I, in the presence of a base(e.g., NEt₃, Hunig's base, etc.) at room temperature to 200° C.,optionally in a sealed container with or without microwave assistance,can give compound 88.

Scheme 19 shows a general scheme for the synthesis of compounds 94 and95, wherein R¹, R^(1a), R², R^(2a), R⁵, R⁶, G and a are as definedherein. A Michael reaction between compounds 89 and 90, wherein Hal isBr, Cl or I, in the presence of an acid (e.g., a protic acid such ascatalytic, concentrated H₂SO₄) gives compound 91. This haloindole 91 maybe converted to an organometallic (e.g., treatment with Sn₂(CH₃)₆,Pd(PPh₃)₄; bispinacol ester boronate, Pd(dppf)Cl₂; or activated Mg)followed by a Pd-mediated coupling with compound 29 using, for example,PdCl₂(PPh₃)₂ and aqueous Na₂CO₃ in dioxane at room temperature to refluxfor a Suzuki coupling, or Ph(PPh₃)₄ in toluene at room temperature toreflux for a Stille coupling, gives compound 92. Reduction of the nitrogroup in 92 using, for example, Fe/AcOH or hydrogenation under a PtO₂catalyst gives the primary amine 93. Optional functionalization of thisamine (e.g., reductive amination, alkylation, etc.) followed byseparation of the two diastereomers then gives compounds 94 and 95.

Scheme 20 describes the preparation of compound 108, wherein R¹, R^(1a),R², R^(2a), R⁵, R⁶ and G are as defined herein. Acylation of 96, whereinHal is Br, Cl or I, with oxalyl chloride, followed by treatment of theresulting acid chloride with a Lewis acid, such as A1Cl₃, gives compound97, which may then be treated with aqueous ammonium hydroxide and anoxidant, such as hydrogen peroxide, to afford the primary amide 98.Hydrolysis of amide 98 with a base, for example, NaOH, yields carboxylicacid 99 (a procedure is described in J. Med. Chem., 37, 2308-2314(1994)). Compound 99 is coupled with N,O-dimethylhydroxylamine understandard coupling conditions (e.g., HBTU, DIEA) to produce the amide101. Compound 101 can react with compound 102, which is a Grignardreagent, zinc or a lithium anion, to produce the ketone 103. Anolefination reaction of compound 103 (e.g., withmethyltriphenylphosphonium bromide in the presence of a base (forexample, Nall, KOBut or NaN(Si(CH₃)₃)₂)) leads to the olefin 104, whichis reacted with allylamine in an organic solvent, for example DMF, togive compound 105. Removal of the allyl group, for example, by treatmentwith 1,3-dimethylpyrimidine-2,46(1H,3H,5H)-trione in the presence ofPd(PPh₃)₄, followed by reprotection of the free amine with anappropriate amine protecting group, for example, Boc, using Boc₂O, givescompound 106, wherein PG is an amine protecting group. Compound 106 maythen be converted to an appropriate organometallic reagent by treatmentwith, for example, a borane, PdCl₂(dppf) and KOAc in DMF, Sn₂(CH₃)₆ andPd(PPh₃)₄ or alternatively an activated form of Mg or Zn. Thisorganometallic reagent may then be coupled to the halopyrimidine 29,wherein Hal is Br, Cl or I, using a palladium-mediated reaction (e.g.,PdCl₂(dppf) and aqueous Na₂CO₃ in, for example, DMF at room temperatureto reflux) to give compound 107. Removal of protecting groups followedby final functionalization of the unprotected free amine (e.g.,alkylation or reductive amination to introduce new substituents) givesrise to the final compound 108. These analogues may then be subject toseparation techniques to give the single diastereomers.

In preparing compounds of Formula I, protection of remotefunctionalities (e.g., primary or secondary amines, etc.) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups (NH-Pg)include acetyl, trifluoroacetyl, Boc, benzyloxycarbonyl (CBz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

Methods of Separation

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by the techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (SMB) and preparative thin or thick layer chromatography, aswell as techniques of small scale thin layer and flash chromatography.One skilled in the art will apply techniques most likely to achieve thedesired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.,(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111).

By method (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (“Chiral LiquidChromatography” (1989) W. J. Lough, Ed., Chapman and Hall, New York;Okamoto, J. of Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

Administration and Pharmaceutical Formulations

The compounds of the invention may be administered by any convenientroute appropriate to the condition to be treated. Suitable routesinclude oral, parenteral (including subcutaneous, intramuscular,intravenous, intraarterial, intradermal, intrathecal and epidural),transdermal, rectal, nasal, topical (including buccal and sublingual),vaginal, intraperitoneal, intrapulmonary and intranasal.

The compounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches, etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, (8^(th) Ed. 2004); Alfonso R. Gennaro et al.,Remington: The Science and Practice of Pharmacy, (20^(th) Ed. 2000); andRaymond C. Rowe, Handbook of Pharmaceutical Excipients, (5^(th) Ed.2005). The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents, diluents and other known additives to providean elegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

One embodiment of the present invention includes a pharmaceuticalcomposition comprising a compound of Formula I, or a stereoisomer orpharmaceutically acceptable salt thereof. In a further embodiment, thepresent invention provides a pharmaceutical composition comprising acompound of Formula I, or a stereoisomer or pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier orexcipient.

Methods of Treatment with Compounds of the Invention

The invention includes methods of treating or preventing disease orcondition by administering one or more compounds of this invention, or astereoisomer or pharmaceutically acceptable salt thereof. In oneembodiment, a human patient is treated with a compound of Formula I, ora stereoisomer or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle in an amountto detectably inhibit AKT activity.

In another embodiment of the present invention, a method of treating ahyperproliferative disease in a mammal comprising administering atherapeutically effective amount of the compound of Formula I, or astereoisomer or pharmaceutically acceptable salt thereof, to the mammalis provided.

In another embodiment, a method of treating or preventing cancer in amammal in need of such treatment, wherein the method comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula I, or a stereoisomer or pharmaceutically acceptablesalt thereof. The cancer is selected from breast, ovary, cervix,prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC),small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma,pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's and leukemia. Another embodiment of the present inventionprovides the use of a compound of Formula I, or a stereoisomer orpharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of cancer.

In another embodiment, a method of treating or preventing a disease ordisorder modulated by AKT, comprising administering to a mammal in needof such treatment an effective amount of a compound of Formula I, or astereoisomer or pharmaceutically acceptable salt thereof. Examples ofsuch diseases and disorders include, but are not limited to, (1)Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (2)Lung: bronchogenic carcinoma (squamous cell, undifferentiated smallcell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma, non-small cell lung, small celllung; (3) Gastrointestinal: esophagus (squamous cell carcinoma,adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); (4) Genitourinary tract: kidney (adenocarcinoma, Wilm'stumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); (5) Liver: hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma; (6) Bone: osteogenic sarcoma (osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma,malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginousexostoses), benign chondroma, chondroblastoma, chondromyxofibroma,osteoid osteoma and giant cell tumors; (7) Nervous system: skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastomamultiform. oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); (8)Gynecological: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma[serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); (9)Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin:advanced melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, keloids, psoriasis; (11) Adrenal glands:neuroblastoma; (12) Breast: metastatic breast; breast adenocarcinoma;(13) Colon; (14) Oral cavity; (15) Hairy cell leukemia; (16) Head andneck; (17) and others including refractory metastatic disease; Kaposi'ssarcoma; Bannayan-Zonana syndrome; and Cowden disease orLhermitte-Duclos disease, among other kinds of hyperproliferativedisorders.

Compounds and methods of this invention can be also used to treatdiseases and conditions such as rheumatoid arthritis, osteoarthritis,Crohn's disease, angiofibroma, ocular diseases (e.g., retinalvascularisation, diabetic retinopathy, age-related macular degeneration,macular degeneration, etc.), multiple sclerosis, obesity, restenosis,autoimmune diseases, allergy, asthma, endometriosis, atherosclerosis,vein graft stenosis, peri-anastomatic prothetic graft stenosis, prostatehyperplasia, chronic obstructive pulmonary disease, psoriasis,inhibition of neurological damage due to tissue repair, scar tissueformation (and can aid in wound healing), multiple sclerosis,inflammatory bowel disease, infections, particularly bacterial, viral,retroviral or parasitic infections (by increasing apoptosis), pulmonarydisease, neoplasm, Parkinson's disease, transplant rejection (as animmunosupressant), septic shock, etc.

Another embodiment of the present invention provides the use of acompound of Formula I, or a stereoisomer or pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for the treatment ofhyperproliferative diseases. In a further embodiment, the presentinvention provides the use of a compound of Formula I, or a stereoisomeror pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of cancer. In a further embodiment, thecancer is selected from carcinoma, lymphoma, blastoma, sarcoma, andleukemia or lymphoid malignancies. More particular examples of suchcancers include squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinomaof the lung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial or uterine carcinoma, salivary gland carcinoma,kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma, anal carcinoma, penile carcinoma, skin cancer,including melanoma, as well as head and neck cancer.

Combination Therapy

The compounds of this invention and stereoisomers and pharmaceuticallyacceptable salts thereof may be employed alone or in combination withother therapeutic agents for treatment. The compounds of the presentinvention can be used in combination with one or more additional drugs,for example an anti-inflammatory compound that works by a differentmechanism of action. The second compound of the pharmaceuticalcombination formulation or dosing regimen preferably has complementaryactivities to the compound of this invention such that they do notadversely affect each other. Such molecules are suitably present incombination in amounts that are effective for the purpose intended. Thecompounds may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. Such sequentialadministration may be close in time or remote in time.

EXAMPLES

In order to illustrate the invention, the following Examples areincluded. However, it is to be understood that these Examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other compounds of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the Examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, andwere used without further purification unless otherwise indicated.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters) (unless otherwise stated). ¹H NMR spectra were recorded on aVarian instrument operating at 400 MHz. ¹H-NMR spectra were obtained asCDCl₃ [using chloroform (7.25 ppm) as the reference standard] d₆-DMSO[using DMSO (2.50 ppm) as the reference standard], CH₃OD [using methanol(3.31 ppm) as the reference standard] or d₆-acetone [using acetone (2.05ppm) as the reference standard] solutions (reported in ppm).Alternatively, tetramethylsilane can be used as an internal referencestandard (0.00 ppm). When peak multiplicities are reported, thefollowing abbreviations are used: s (singlet), d (doublet), t (triplet),q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt(doublet of triplets). Coupling constants, when given, are reported inHertz (Hz).

Example A AKT-1 Kinase Assay

The activity of the compounds described in the present invention may bedetermined by the following kinase assay, which measures thephosphorylation of a fluorescently-labeled peptide by full-length humanrecombinant active AKT-1 by fluorescent polarization using acommercially available IMAP kit.

The assay materials are obtained from an IMAP AKT Assay Bulk Kit,product #R8059, from Molecular Devices, Sunnyvale, Calif. The kitmaterials include an IMAP Reaction Buffer (5×). The diluted 1×IMAPReaction Buffer contained 10 mM Tris-HCl, pH 7.2, 10 mM MgCl₂, 0.1% BSA,0.05% NaN₃. DTT is routinely added to a final concentration of 1 mMimmediately prior to use. Also included is IMAP Binding Buffer (5×), andIMAP Binding Reagent. The Binding Solution is prepared as a 1:400dilution of IMAP Binding Reagent into 1×IMAP Binding Buffer.

The fluorescein-labeled AKT Substrate (Crosstide) has the sequence(F1)-GRPRTSSFAEG. A stock solution of 20 μM is made up in 1×IMAPReaction Buffer.

The plates used include a Costar 3657 (382-well made of polypropyleneand having a white, v-bottom) that is used for compound dilution and forpreparing the compound-ATP mixture. The assay plate is a PackardProxyPlate™-384 F.

The AKT-1 used is made from full-length, human recombinant AKT-1 that isactivated with PDK1 and MAP kinase 2.

To perform the assay, stock solutions of compounds at 10 mM indimethylsulfoxide (“DMSO”) are prepared. The stock solutions and thecontrol compound are serially diluted 1:2 nine times into DMSO (10 μL ofcompound+10 μL of DMSO) to give 50× dilution series over the desireddosing range. Next, 2.1-μL aliquots of the compounds in DMSO aretransferred to a Costar 3657 plate containing 50 μL of 10.4 μM ATP in1×IMAP Reaction Buffer containing 1 mM DTT. After thorough mixing, 2.5-4aliquots are transferred to a ProxyPlate™-384 F plate.

The assay is initiated by the addition of 2.5-μL aliquots of a solutioncontaining 200 nM of fluorescently-labeled peptide substrate and 4 nMAKT-1. The plate is centrifuged for 1 minute at 1000 g and incubated for60 minute at ambient temperature. The reaction is then quenched by theaddition of 15 μL of Binding Solution, centrifuged again and incubatedfor an additional 30 minutes at ambient temperature prior to reading ona Victor 1420 Multilabel HTS Counter configured to measure fluorescencepolarization.

Representative compounds were tested in the above assay and found tohave IC₅₀ values of less than 10 μM.

Example 1

(5R,7R)-4-(4-((S)-(4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

Step 1: tert-Butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate (3.63 g,11.2 mmol) was dissolved in ethanol (100 mL) then sodiumtetrahydroborate (424 mg, 112 mmol) was added to this solution. Thereaction mixture was stirred at room temperature for 3 h. LC-MS analysisof the reaction mixture showed no more starting material. The crudereaction mixture was concentrated and the residue was diluted with EtOAc(100 mL) and washed with water (2×50 mL) and brine (50 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated to yieldtert-butyl 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate(3.46 g, 94%), which was used in the next step directly. m/z: 326 (MH⁺)

Step 2: To a solution of tert-butyl4-((4-chlorophenyl)(hydroxyl)methyl)piperidine-1-carboxylate (1.25 g,3.84 mmol) in DMF (50 mL) was added sodium hydride 60% w/w dispersion onmineral oil (384 mg, 9.59 mmol). The reaction mixture was stirred for 10minutes at room temperature then 2-chloro-N,N-dimethylethanaminehydrochloride (608 mg, 4.22 mmol) ws added. The reaction mixture wasstirred at 70° C. for 12 h. LC-MS of the reaction mixture showed no morestarting material. The reaction mixture was cooled to room temperatureand was diluted with EtOAc (50 mL) and washed with 10% LiCl in water(2×50 mL) followed by water (50 mL) and brine (50 mL). The organic layerwas dried over Na₂SO4, filtered and concentrated to yield tert-butyl4-((4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidine-1-carboxylatethat was purified by reversed phase HPLC followed by separation onenantiomers by SFC. (253 mg and 246 mg, 33%) m/z: 397 (MH⁺)

Step 3: To a solution of tert-butyl4-((4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidine-1-carboxylate(156 mg, 0.39 mmol) in methanol (1 mL) was added a solution of 4N HCl ondioxane (1 mL, 4.0 mmol). The reaction mixture was stirred at roomtemperature for 2 h. LC-MS of the reaction mixture showed no morestarting material. The solvent was removed and the(S)-2-((4-chlorophenyl)(piperidin-4-yl)methoxy)-N,N-dimethylethanaminewas used in the next step without further purification. m/z: 297 (MH⁺)

Step 4: To a solution of(5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (65 mg, 0.196 mmol) in THF (1 mL) and water (1 mL) at 0°C. was added lithium hydroxide (19 mg, 0.39 mmol). The reaction mixturewas stirred at 0° C. for 30 minutes then it was warmed up to roomtemperature and stirred for 2 h. LC-MS analysis of the reaction mixtureshowed no more starting material. THF was removed and water was added (5mL). The residue was extracted with EtOAc (3×10 mL). The combinedorganic layers were washed with NaHCO₃ (10 mL), brine (10 mL), driedover Na₂SO₄, filtered and concentrated. The crude product was dilutedwith 1-butanol (2 mL) and crude(S)-2-((4-chlorophenyl)(piperidin-4-yl)methoxy)-N,N-dimethylethanaminewas added followed by DIPEA (0.39 mL, 2.2 mmol). The reaction mixturewas heated to 135° C. and was stirred for 4 h. LC-MS of the reactionmixture showed no more starting material. The solvent was evaporated andthe residue was purified on silica gel (0%-6% 2N NH₃ in MeOH/DCM)gradient elution to yield(5R,7R)-4-(4((S)-(4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olas a foam (78 mg, 98%). m/z: 445 (M^(+l );) ¹H NMR (DMSO d₆): 9.33 (brs, 1H), 8.61 (s, 1H), 7.48 (d, 2H, J=8.2 Hz), 7.34 (d, 2H, J=8.2 Hz),5.14-5.11 (m, 1H), 4.69-4.66 (m, 1H), 4.41-4.39 (m, 1H), 4.16-4.14 (m,1H), 3.45-3.04 (m, 7H), 2.81-2.75 (m, 6H), 2.13-2.00 (m, 4H), 1.39-1.70(m, 3H), 1.11 (d, 3H, J=6.8 Hz).

Example 2

(5R,7R)-4-(4-((R)-(4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

To a solution of(5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (65 mg, 0.196 mmol) in THF (1 mL) and water (1 mL) at 0°C. was added lithium hydroxide (19 mg, 0.39 mmol). The reaction mixturewas stirred at 0° C. for 30 minutes then it was warmed up to roomtemperature and stirred for 2 h. LC-MS analysis of the reaction mixtureshowed no more starting material. THF was removed and water was added (5mL). The residue was extracted with EtOAc (3×10 mL). The combinedorganic layers were washed with NaHCO₃ (10 mL), brine (10 mL), driedover Na₂SO₄, filtered and concentrated. The crude product was dilutedwith 1-butanol (2 mL) and crude(R)-2-((4-chlorophenyl)(piperidin-4-yl)methoxy)-N,N-dimethylethanaminewas added followed by DIPEA (0.39 mL, 2.2 mmol). The reaction mixturewas heated to 135° C. and was stirred for 4 h. LC-MS of the reactionmixture showed no more starting material. The solvent was evaporated andthe residue was purified on silica gel (0%-6% 2N NH₃ in MeOH/DCM)gradient elution to yield(5R,7R)-4-(4-((R)-(4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olas a white foam (78 mg, 98%). m/z: 445 (M⁺); ¹H NMR (DMSO d₆) δ (ppm)9.46 (br s, 1H), 8.63 (s, 1H), 7.48 (d, 2H, J=8.0 Hz), 7.35 (d, 2H,J=8.1 Hz), 5.18-5.15 (m, 1H), 4.59-4.55 (m, 2H), 4.20-4.16 (m, 1H),3.58-3.24 (m, 6H), 3.03-2.98 (m, 1H), 2.81-2.75 (m, 6H), 2.14-2.01 (m,4H), 1.36-1.21 (m, 3H), 1.13 (d, 3H, J=6.9 Hz).

Example 3

N-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-54(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide

Step 1: (R)-(+)-Pulegone (76.12 g, 0.5 mmol), anhydrous NaHCO₃ (12.5 g)and anhydrous ether (500 mL) were added to a 1 L round-bottom flask. Thereaction mixture was cooled with an ice-bath under nitrogen. Bromine(25.62 mL, 0.5 mmol) was added dropwise over 30 minutes. The mixture wasfiltered and carefully added to NaOEt (21%, 412 mL, 1.11 mmol) in anice-cooled bath. The mixture was stirred at room temperature overnight,and then 5% HCl (1 L) and ether (300 mL) were added. The aqueous phasewas extracted with ether (2×300 mL). The combined organic phase waswashed with water, dried and concentrated. The residue was added to awarmed solution of semicarbazide hydrochloride (37.5 g) and NaOAc (37.5g) in water (300 mL). Then boiling ethanol (300 mL) was added to give aclear solution. The mixture was refluxed for 2.5 hours and then stirredat room temperature overnight. The mixture was treated with water (1 L)and ether (300 mL). The aqueous phase was extracted with ether (2×300mL). The combined organic phase was washed with water, dried andconcentrated. The residue was purified by vacuum distillation (73-76° C.at 0.8 mm Hg) to give (2R)-ethyl2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (63 g, 64%). ¹H NMR(CDCl₃, 400 MHz) δ 4.13 (m, 2H), 3.38 (d, J=16 Hz, 0.5H), 2.93 (m,0.5H), 2.50-2.17 (m, 2H), 1.98 (m, 1H), 1.76 (m, 1H), 1.23 (m, 6H), 1.05(m, 6H).

Step 2: (2R)-Ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate(24 g, 0.122 mol) in ethyl acetate (100 mL) was cooled to −68° C. withdry ice/isopropanol. Ozonized oxygen (5-7 ft³h⁻¹ of O₂) was bubbledthrough the solution for 3.5 hours. The reaction mixture was flushedwith nitrogen at room temperature until the color disappeared. The ethylacetate was removed under vacuum, and the residue was dissolved inacetic acid (150 mL) and cooled by ice water. Zinc powder (45 g) wasthen added. The solution was stirred for 30 minutes and then filtered.The filtrate was neutralized with 2N NaOH (1.3 L) and NaHCO₃. Theaqueous phase was extracted with ether (3×200 mL). The organic phase wascombined, washed with water, dried and concentrated to afford (2R)-ethyl2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%). ¹H NMR (CDCl₃, 400MHz) δ 4.21 (m, 2H), 2.77 (d, J=11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2.10(m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 1.23 (m, 3H).

Step 3: KOH (8.3 g, 147.9 mmol) in water (60 mL) was added to a solutionof a mixture of (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (20 g,117.5 mmol) and thiourea (9.2 g, 120.9 mmol) in ethanol (100 mL). Themixture was refluxed for 10 hours. After cooling, the solvent wasremoved, and the residue was neutralized with concentrated HCl (12 mL)at 0° C. The mixture was then extracted with DCM (3×150 mL). The solventwas removed, and the residue was purified by silica gel chromatography,eluting with hexane/ethyl acetate (2:1) to give(R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12g, 56%). MS (APCI+) [M+H]⁺183.

Step 4: Raney Nickel (15 g) and NH₄OH (20 mL) were added to a suspensionof (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol(12 g, 65.8 mmol) in distilled water (100 mL). The mixture was refluxedfor 3 hours and then filtered. The filtrate was concentrated to afford(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.89 g, 99%).MS (APCI+) [M+H]⁺151.

Steps 5 and 6 describe an alternate synthesis of(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol, starting from(R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate.

Step 5: Ammonium acetate (240 g, 3110 mmol) was added to a solution of(R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (106 g, 623 mmol) inMeOH (1.2 L). The reaction mixture was stirred at room temperature undernitrogen for 20 hours, after which it was complete as determined by TLCand HPLC. The reaction mixture was concentrated to remove MeOH. Theresulting residue was dissolved in DCM, washed twice with H₂O, once withbrine, dried (Na₂SO₄), filtered, and concentrated to give (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate (102 g, 97% yield) as an oil.LC/MS (APCI+) m/z 170 [M+H]+.

Step 6: A solution containing (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate (161.6 g, 955 mmol) andammonium formate (90.3 g, 1433 mmol) in formamide (303.5 mL, 7640 mmol)was heated to an internal temperature of 150° C. and stirred for 17hours. The reaction mixture was cooled, and transferred to a 2 L singlenextracted flask. Excess formamidine was then removed by high vacuumdistillation. Once formamidine stopped coming over, the remaining oil inthe still pot was dissolved in DCM and washed with brine (3×200 mL). Thecombined aqueous washes were extracted with DCM. The combined organicextracts were dried (Na₂SO₄), filtered, and concentrated. The resultingoil was dissolved in minimal DCM, and this solution was added using aseparatory funnel to a stirred solution of ether (about 5 volumes ofether vs. DCM solution), causing some precipitate to form. Thisprecipitate was removed by filtration through a medium frit funnel whichwas rinsed with ether and disposed. The filtrate was concentrated, thetrituration from ether repeated two more times and then dried on highvacuum line to give(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (93.2 g, 65.0%yield) as a pasty solid. LC/MS (APCI−) m/z 149.2.

Step 7: A mixture of(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (5.8 g, 38.6mmol) in POCl₃ (20 mL) was refluxed for 5 minutes. Excess POCl₃ wasremoved under vacuum, and the residue was dissolved in DCM (50 mL). Themixture was then added to a saturated NaHCO₃ solution (200 mL). Theaqueous phase was extracted with DCM (3×100 mL), and the combinedorganic phases were dried and concentrated. The resulting residue waspurified by silica gel chromatography, eluting with ethyl acetate togive (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.18g, 49%). ¹H NMR (CDCl₃, 400 MHz) δ □8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m,1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).

Step 8: Pd(PPh₃)₄ (10 mg, 0.09 mmol) was added to a degassed solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta-[d]-pyrimidine (300 mg,1.78 mmol) and a 0.5M solution of 5-ethoxycarbonyl-2-thienylzinc bromidein THF (3.6 mL, 1.78 mmol). The reaction mixture was stirred at 70° C.for 16 hours and then it was cooled to room temperature and diluted withdiethyl ether (10 mL). Water was added (5 mL) and a precipitate wasformed and filtered. The solid was washed with more diethyl ether andthe filtrate was concentrated. The resulting oil was purified on silicagel (0%-75% EtOAc/hexanes) to yield (R)-ethyl5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylateas an oil (400 mg, 78%). m/z: 289 (MH+), ¹H NMR (CDCl₃): δ (ppm) 8.95(s, 1H), 7.84-7.82 (m, 1H), 7.70-7.69 (m 1H), 4.39 (dq, 2H, J1=7.2 Hz,J2=1.2 Hz), 3.77 (quint., 1H, J=7.2 Hz), 3.23-1.14 (m, 1H), 3.001-2.95(m, 1H), 2.42-2.31 (m, 1H), 1.98-1.92 (m, 1H), 1.40 (dt, 3H, J1=7.2 Hz,J2=1.2 Hz), 1.29 (d, 3H, J=7.2 Hz).

Step 9: A 1N solution of sodium hydroxide in water (2.4 mL) was added toa solution of (R)-ethyl5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylate(236 mg, 0.818 mmol) in ethanol (2.5 mL). The reaction mixture wasstirred at room temperature for 16 hours. LC-MS analysis of the reactionmixture showed no more starting material. Water (5 mL) was added, andthe solution was acidified with 1N HCl (1 mL) and extracted with EtOAc(3×5 mL). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The resulting(R)-5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylicacid was used without further purification. m/z: 261 (MH+).

Step 10: A solution of lithium tetrahydroborate (190 mg, 8.50 mmol) inTHF (4 mL) was cooled to 0° C. Chlorotrimethylsilane (2.2 mL, 17 mmol)was added dropwise. The mixture was stirred for 20 minutes at roomtemperature and then returned to 0° C.(S)-2-amino-3-(2,4-dichlorophenyl)propanoic acid (1.00 g, 4.27 mmol) wasthen added. The reaction was allowed to warm up slowly to roomtemperature while stirring overnight. The mixture was cooled to 0° C.and quenched by slow addition of methanol (1 mL) followed by an aqueoussolution of 2N sodium hydroxide (4.2 mL, 8.54 mmol). Volatiles wereremoved under reduces pressure. The slurry was diluted with water (5 mL)and extracted with DCM (3×15 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated toafford (S)-2-amino-3-(2,4-dichlorophenyl)propan-1-ol as a solid that wasused in the next step without further purification. MS m/z 220 (M+).

Step 11: di-tert-Butyldicarbonate (850 mg, 3.90 mmol) was added to asolution of (S)-2-amino-3-(2,4-dichlorophenyl)propan-1-ol (859 mg, 3.90mmol) in CHCl₃ (10 mL). The reaction mixture was stirred at roomtemperature for 18 hours. LC-MS analysis of the reaction mixture showedno more starting material. The solvent was removed under reducedpressure, and the resulting residue was purified on silica gel (49:49:2DCM: EtOAc: MeOH) to yield (S)-tert-butyl1-(2,4-dichlorophenyl)-3-hydroxypropan-2-ylcarbamate as a solid (1.17 g,94%). MS m/z 320 (M+); ¹H NMR (CDCl₃): δ (ppm) 7.38 (s, 1H), 7.23-7.17(m, 2H), 4.84-4.82 (m, 1H), 3.95-3.87 (m, 1H), 3.74-3.68 (m, 1H),3.63-3.55 (m, 1H), 3.02-2.98 (m, 2H), 2.31 (br s, 1H), 1.39 (s, 9H).

Step 12: A solution of (S)-tert-butyl1-(2,4-dichlorophenyl)-3-hydroxypropan-2-ylcarbamate (50 mg, 0.156 mmol)in DCM (1 mL) was cooled to 0° C. Triethylamine (24 μL, 0.172 mmol) wasadded, followed by methanesulfonyl chloride (24 μL, 0.312 mmol). Thereaction mixture was allowed to warm up slowly to room temperature andwas stirred for 4 hours. TLC analysis of the reaction mixture showed nomore starting material. Diethyl ether was added, and the precipitate wasfiltered. The filtrate was concentrated, and the resulting residue wasdiluted with DMF (0.5 mL), and sodium azide (51 mg, 0.781 mmol) wasadded. The reaction mixture was heated to 100° C. for 16 hours. LC-MS ofmixture showed no more starting material. Water was added (5 mL), andthe reaction mixture was extracted with diethyl ether (3×5 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified on silica gel(0%-70% EtOAc/hexanes gradient elution to yield (S)-tert-butyl1-azido-3-(2,4-dichlorophenyl)propan-2-ylcarbamate as an oil (32 mg,59%). m/z 345 (M+); ¹H NMR (CDCl₃) δ (ppm) 7.39 (s, 1H), 7.21-7.17 (m,2H), 4.71-4.68 (m, 1H), 4.07-4.02 (m, 1H), 3.52-3.38 (m, 2H), 2.95-2.86(m, 2H), 1.38 (s, 9H).

Step 13: TFA (0.56 mL, 7.24 mmol) was added to a solution of(S)-tert-butyl 1-azido-3-(2,4-dichlorophenyl)propan-2-ylcarbamate (100mg, 0.290 mmol) in DCM (2 mL). The reaction mixture was stirred at roomtemperature for 1 hour. LC-MS of the reaction mixture showed no morestarting material. The solvent was removed, and the residue wasco-evaporated with toluene (3×10 mL). The(S)-1-azido-3-(2,4-dichlorophenyl)propan-2-amine was carried to the nextstep without further purification. m/z 246 (MH+).

Step 14: (S)-1-Azido-3-(2,4-dichlorophenyl)propan-2-amine (33 mg, 0.134mmol) was added to a solution of(R)-5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylicacid (35 mg, 0.134 mmol) in DCM (0.7 mL). HBTU (56 mg, 0.148 mmol) wasadded, followed by DIPEA (0.23 mL, 1.34 mmol). The reaction mixture wasstirred at room temperature for 1 hour. LC-MS of the reaction mixtureshowed no more starting material. The solvent was removed, and theresulting residue was purified on silica gel (0%-50% EtOAc/hexanes)gradient elution to yieldN-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamideas an oil (59 mg, 90%). m/z 486 (MH+).

Step 15: 10% Pd/C (6 mg) was added to a solution ofN-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide(59 mg, 0.121 mmol) in methanol (2.5 mL). The solution was put undervacuum and purged with H₂ (3×), and then the reaction mixture wasstirred under a hydrogen atmosphere for 2 hours. LC-MS analysis of thereaction mixture showed no more starting material. The reaction mixturewas filtered and concentrated to yieldN-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamideas a foam (53 mg, 95%). m/z 461 (M+); ¹H NMR (DMSO d₆) δ (ppm) 8.91 (s,1H), 8.58-8.56 (m, 1H), 7.90 (br s, 2H), 7.84 (d, 1H, J=4.3 Hz), 7.78(d, 1H, J=4.1 Hz), 7.60 (m, 1H), 7.39-7.33 (m, 2H), 4.55-4.42 (m, 1H),3.87-3.77 (m, 1H), 3.19-2.84 (m, 6H), 2.33-2.26 (m, 1H), 1.88-1.82 (m,1H), 1.18 (d, 3H, J=6.9 Hz).

Example 4

N-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide

Step 1: m-CPBA (1.06 g, 6.12 mmol) was added portionwise to a solutionof (R)-methyl5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylate(883 mg, 3.06 mmol) in CHCl₃ (20 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 10 minutes then it was warmed up to roomtemperature and stirred for 18 hours. LC-MS analysis of the reactionmixture showed no more starting material. The reaction mixture wascooled to 0° C., and a solution of Na₂S₂O₃ (968 mg, 6.12 mmol) in water(5 mL) was added dropwise, followed by a solution of Na₂CO₃ (649 mg,6.12 mmol) in water (10 mL). The reaction mixture was stirred for 30minutes at 0° C., and then it was warmed up to room temperature andextracted with CHCl₃ (3×25 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give theN-oxide as an oil. The crude product was dissolved in acetic anhydride(5.8 mL, 61.2 mmol), and the solution was heated to 90° C. for 2 hours.The excess acetic anhydride was then removed under reduced pressure, andthe residue was dissolved in DCM (20 mL) and poured slowly into astirred aqueous saturated solution of Na₂CO₃ cooled to 0° C. The mixturewas extracted with DCM (3×10 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated to yieldan oil. The oil was dissolved in THF (15 mL), and a solution of LiOH(366 mg, 7.65 mmol) in water (2.2 mL) was added. The reaction mixturewas stirred at room temperature under N₂ for 16 hours. LC-MS analysis ofthe reaction mixture showed no more starting material. Water was added(10 mL), and the reaction mixture was extracted with EtOAc (3×10 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to yield a solid that was purified by reversedphase HPLC to give(R)-5-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylicacid (336 mg, 40%) as a mixture of diastereoisomers. m/z 277 (MH⁺).

Step 2: Trimethylsilyldiazomethane (1.10 mmol) was added dropwise to asuspension of(R)-5-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylicacid (200 mg, 0.723 mmol) in MeOH (5 mL) and Et₂O (5 mL). The reactionmixture was stirred for 1 hour at room temperature, and then the solventwas removed under reduced pressure. The residue was diluted with DCM (10mL) and then cooled to 0° C. Triethylamine (131 μL, 0.94 mmol) wasadded, followed by the addition of p-nitrobenzoyl chloride (148 mg,0.792 mmol). The reaction mixture was allowed to warm up slowly to roomtemperature and was stirred for 4 hours. TLC analysis of the reactionmixture showed no more starting material. The reaction mixture wasquenched by the addition of saturated aqueous solution of NaHCO₃ (5 mL),and the reaction mixture was extracted with DCM (3×10 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified on silica gel (10%-45%EtOAc/hexanes) gradient elution to yield5-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylateas a solid (32 mg, 10%). m/z 440 (MH⁺); ¹H NMR (CDCl₃) δ (ppm) 9.12 (s,1H), 8.31-8.26 (m, 4H), 7.87 (d, 1H, J=4.0 Hz), 7.76 (d, 1H, J=4.0 Hz),6.63 (dd, 1H, J₁=7.7 Hz, J₂=7.8 Hz), 3.95 (s, 3H), 2.71-2.65 (m, 1H),2.51-2.43 (m, 1H), 1.43 (d, 3H, J=7.1 Hz).

Step 3: Lithium hydroxide (6 mg, 0.146 mmol) was added to a solution of5-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylate(32 mg, 0.073 mmol) in THF (0.5 mL) and water (0.5 mL). The reactionmixture was stirred at room temperature for 1 hour. LC-MS of thereaction mixture showed no more starting material. THF was removed underreduced pressure, and 1N HCl (5 mL) was added. The reaction mixture wasextracted with EtOAc (3×5 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylicacid. The crude mixture was used directly in the next step withoutfurther purification.

Step 4: (S)-1-Azido-3-(2,4-dichlorophenyl)propan-2-amine (20 mg, 0.0724mmol) was added to a solution of5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylicacid (35 mg, 0.145 mmol) in DCM (0.5 mL). DMF (125 μL) was added tosolubilize the starting material completely. DIPEA (126 μL, 0.724 mmol)was added, followed by the addition of HBTU (30 mg, 0.079 mmol). Thereaction mixture was stirred at room temperature for 1 hour. LC-MS ofthe reaction mixture showed no more starting material. The solvent wasremoved, and the resulting residue was purified by reversed phase HPLCto yieldN-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamideproduct as a solid (4 mg, 10%). m/z 504 (MH⁺).

Step 5: 10% w/w Pd/C (1 mg) was added to a solution ofN-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide(4.0 mg, 0.008 mmol) in MeOH (0.5 mL). The solution was put under vacuumand purged with H₂ (3×). The reaction mixture was then stirred under ahydrogen atmosphere for 2 hours. LC-MS analysis of the reaction mixtureshowed no more starting material. The reaction mixture was filtered andthen concentrated to yieldN-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamideas a solid (3.7 mg, 98%). m/z 477 (M⁺). ¹H NMR (DMSO d₆) δ (ppm) 8.91(s, 1H), 8.58-8.56 (m, 1H), 7.90 (br s, 2H), 7.84 (d, 1H, J=4.3 Hz),7.78 (d, 1H, J=4.1 Hz), 7.60 (m, 1H), 7.39-7.33 (m, 2H), 5.22-5.17 (m,1H), 4.59-4.50 (m, 1H), 3.87-3.77 (m, 1H), 3.19-2.84 (m, 5H), 2.33-2.26(m, 1H), 1.88-1.82 (m, 1H), 1.13 (d, 3H, J=6.9 Hz).

Example 5

(5R,7R)-4-(4-(4-(4-chlorophenyl)piperidin-4-yl)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

Step 1: Ammonium acetate (240 g, 3110 mmol) was added to a solution of(R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (106.0 g, 622.8 mmol) inMeOH (1.2 L). The reaction mixture was stirred at room temperature undernitrogen for 20 hours. The reaction was complete as determined by TLCand HPLC. The reaction mixture was concentrated to remove MeOH. Theresulting residue was dissolved in DCM, washed twice with H₂O, once withbrine, dried (Na₂SO₄), filtered, and concentrated to give (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate (102 g, 97% yield) as an oil.LC/MS (APCI+) m/z 170 [M+H]+.

Step 2: A solution containing (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate (161.6 g, 955.0 mmol) andammonium formate (90.3 g, 1430 mmol) in formamide (303.5 mL, 7640 mmol)was heated to an internal temperature of 150° C. and stirred for 17hours. The reaction mixture was cooled, and transferred to a 2 L singlenextracted flask. Then excess formamidine was removed by high vacuumdistillation. Once formamidine stopped coming over, the remaining oil inthe still pot was dissolved in DCM and washed with brine (3×200 mL). Thecombined aqueous washes were extracted with DCM. The combined organicextracts were dried (Na₂SO₄), filtered, and concentrated. The resultingoil was dissolved in minimal DCM, and this solution was added using aseparatory funnel to a stirred solution of ether (about 5 volumes ofether vs. DCM solution), causing some precipitate to form. Thisprecipitate was removed by filtration through a medium frit funnel,which was rinsed with ether and disposed. The filtrate was concentrated,the trituration from ether repeated two more times and then dried onhigh vacuum line to give(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (93.23 g, 65.00%yield) as a pasty solid. LC/MS (APCI−) m/z 149.2.

Step 3: Neat POCl₃ (463.9 mL, 5067 mmol) was added slowly by additionfunnel to a 0° C. solution of(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013mmol) in DCE (1.2 L). After the addition was complete, the reactionmixture was warmed to room temperature. The reaction mixture was thenheated to reflux and stirred for 70 minutes. The reaction was completeas determined by HPLC. The reaction mixture was cooled to roomtemperature, and the excess POCl₃ was quenched in 4 portions as follows:The reaction mixture was transferred to a separatory funnel and drippedinto a beaker containing ice and a saturated NaHCO₃ solution cooled inan ice bath. Once the addition of each portion of the reaction mixturewas completed, the quenched mixture was stirred 30 minutes to ensurecomplete destruction of POCl₃ prior to transfer to separatory funnel.The mixture was transferred to the separatory funnel and extracted twicewith DCM. The combined extracts were dried (Na₂SO₄), filtered, andconcentrated. The crude was purified on silica gel as follows: silicagel (1 kg) was slurried in 9:1 hexane:ethyl acetate onto a 3 L flittedfunnel, the silica settled under vacuum and topped with sand. The crudewas loaded with a DCM/hexane mixture, and the compound was eluted using1 L sidearm flasks under vacuum to give(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g,61.09% yield) as an oil.

Step 4: Solid 77% maximum m-CPBA (12 g, 53 mmol) was added portionwiseto a 0° C. solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5 g, 30mmol) in CHCl₃ (80 mL). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was cooled to 0° C., andthen treated by the addition of NaHCO₃ (25 g, 196 mmol) slurry in water(100 mL). This was followed by the dropwise addition of Na₂CO₃ (14 g,128 mmol) in water (100 mL). The reaction mixture was stirred for 30minutes. The aqueous phase was extracted with CHCl₃. The organic phasewas dried with MgSO₄ and concentrated under reduced pressure at lowtemperature (<25° C.) to afford the crude(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide(5.5 g, 100%), which was used in the next step without furtherpurification.

Step 5: A solution of the(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide(5.5 g, 29.8 mmol) in Ac₂O (40.5 mL, 429 mmol) was heated to 110° C. for3 hours. After cooling, the acetic anhydride was evaporated, and theresulting residue was taken up in DCM. This solution was added to astirring cold solution of saturated NaHCO₃. The layers were extractedwith DCM, dried MgSO₄, filtered, and concentrated. The crude oil waschromatographed (Biotage) eluting with 20% EtOAc/hexane, to provide(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (3.0 g, 44.4%).

Step 6: A solution of(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (11.86 g, 52.33 mmol) in 2:1 THF:H₂O (270 mL) was cooled to 0°C. and treated with lithium hydroxide hydrate (3.95 g, 94.2 mmol). Thereaction was stirred at room temperature for 4 hours. The reaction wasconcentrated and diluted with water and acidified with 6N HCl to a pH of6. The aqueous layer was extracted with EtOAc. The combined organicswere washed with brine, dried MgSO₄, filtered, and concentrated. Thecrude residue was chromatographed (Biotage 65) eluting with 30-50%EtOAc/hexane to give(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (6.09g, 63%).

Step 7: Solid 4-nitrobenzoyl chloride (6.73 g, 36.3 mmol) was added to astirred solution of(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (6.09g, 33.0 mmol) and NEt₃ (5.98 mL, 42.9 mmol) in DCM (165 mL) at 0° C. Thereaction was warmed to room temperature and then stirred at roomtemperature for 3 hours. The reaction was diluted with DCM and saturatedaqueous NaHCO₃. The combined extracts were washed with brine, driedMgSO₄, filtered, and concentrated. The crude residue was chromatographedeluting with 10-14% EtOAc/hexane several times to give(5R,7S)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (3.96 g, 36%) and(5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl-4-nitrobenzoate(5.92 g, 54%).

Step 8: n-Butyl lithium (16 mL, 2.5M solution in hexanes, 39.9 mmol) wasadded to a solution of 1-bromo-4-chlorobenzne (8.62 g, 45.0 mmol) inanhydrous THF (100 mL) at −78° C. under nitrogen. After 30 minutes at−78° C., 1-Boc-piperidone (6.62 g, 33.2 mmol) was added dropwise as asolution in anhydrous THF (5 mL). After 30 minutes at −78° C., thereaction was quenched with a saturated NH₄Cl solution (100 mL),extracted with EtOAc (2×100 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude product was purified bysilica gel chromatography, eluting with EtOAc/hexane (0-40%) to givetert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (7.64 g,74% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.38 (d, J=7.2 Hz, 2H), 7.15 (d,J=7.3 Hz, 2H), 3.94 (br s, 2H), 3.18 (br s, 2H), 1.89 (br s, 2H), 1.46(s, 11H). LCMS: M+1 312.2.

Step 9: Solid aluminum trichloride (0.68 mL, 5.1 mmol) was added to asolution of tert-butyl4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (0.40 g, 1.3 mmol)in bromobenzene (5.4 mL, 51.3 mmol) at 0° C. under nitrogen. After beingstirred at 0° C. for 4 hours, the mixture was quenched with ice andconcentrated under reduced pressure. The mixture was dissolved in 1NLiOH (30 mL) and extracted with EtOAc (2×30 mL). The combined organicswere dried with Na₂SO₄, filtered and concentrated. The crude product wasdirectly taken up in EtOAc (4 mL) and aqueous Na₂CO₃ solution (2M, 4mL). Di-tert-butyldicarbonate (0.851 g, 3.9 mmol) was added in oneportion. The mixture was stirred at 23° C. overnight. The next day, twolayers were separated, and the aqueous layer was further extracted withEtOAc (2×10 mL). The combined organics were dried over Na₂SO₄,concentrated, and purified by column chromatography (0-40%EtOAc/hexanes) to give tert-butyl4-(4-bromophenyl)-4-(4-chlorophenyl)piperidine-1-carboxylate (0.302 g,51% yield). ¹H NMR (CDCl₃, 400 MHz) δ 7.46 (d, J=7.2 Hz, 2 H), 7.32 (d,J=6.9 Hz, 2 H), 7.19 (d, J=7.0 Hz, 2 H), 7.12 (d, J=7.3 Hz, 2 H), 3.54(br s, 2H), 2.35 (br s, 2 H), 1.54 (br s, 2H), 1.43 (s, 11H). LCMS: M+1452.2.

Step 10: Bispinacol ester boronate (93 mg, 0.37 mmol) was added undernitrogen to a solution of tert-butyl4-(4-bromophenyl)-4-(4-chlorophenyl)piperidine-1-carboxylate (150 mg,0.33 mmol) in 1,4-dioxane (5 mL) at 23° C. Potassium acetate (98 mg, 1.0mmol) was then added, and finally1,1′-bis(diphenylphosphino)ferrocenepalladium (II) chloride (10 mg, 0.02mmol) was added. The mixture was heated to 100° C. under nitrogen. After3 hours, the reaction was cooled to room temperature, diluted with H₂O(10 mL), and extracted with EtOAc (2×10 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude material waspurified by column chromatography (gradient from 100% hexane to 4:6EtOAc: hexanes) to give the boronate (120 mg, 72% yield).(5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (82 mg, 0.246 mmol) was added to this boronate (120 mg,0.24 mmol), followed by the addition of 1,4-dioxane (3 mL) and aqueousNa₂CO₃ solution (1M, 0.3 mL). The mixture was flushed with nitrogen andbis(triphenylphosphine)palladium(II) chloride (8.6 mg, 0.123 mmol) wasadded in one portion. The mixture was heated at 100° C. under nitrogenfor 12 hours. Then the reaction mixture was diluted with 0.1N LiOHsolution (10 mL) and extracted into EtOAc (2×10 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered, concentrated underreduced pressure, and purified by column chromatography (0-100%EtOAc/hexanes) to give tert-butyl4-(4-chlorophenyl)-4-(4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperidine-1-carboxylate(36 mg, 29% yield) as an oil.

Step 11: tert-Butyl4-(4-chlorophenyl)-4-(4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperidine-1-carboxylate(36 mg, 0.069 mmol) was dissolved in DCM (3 mL) and cooled to 0° C. ThenTFA (1.5 mL) was added dropwise. The resulting solution was stirred at0° C. for 1 hour, concentrated under reduced pressure, dissolved in DMF(1 mL) and purified by reverse phase HPLC (0-100% AcCN/H₂O) to give(5R,7R)-4-(4-(4-(4-chlorophenyl)piperidin-4-yl)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldi-TFA salt (9 mg, 31% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.09 (s, 1H), 7.88 (d, J=8.8 Hz, 2 H), 7.52 (d, J=8.4 Hz, 2 H), 7.42 (q, J=4.8 Hz,4 H), 5.64 (d, J=6.0 Hz, 1H), 5.06 (q, J=6.8 Hz, 1H), 3.85 (br s, 1H),3.05 (br s, 3H), 2.89 (m, 2H), 2.61 (br s, 3H), 2.11 (m, 2H), 1.16 (t,J=6.4 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H). LCMS: M+1 420.4.

Example 6

N-((R)-2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethyl)propan-2-amine

Step 1: 1-((1E)-2-Nitrovinyl)-4-chlorobenzene (0.206 g, 1.12 mmol) wasadded to a solution of 6-bromoindole (0.200 g, 1.02 mmol) in methanol (5mL), followed by the addition of sufamic acid (39.6 mg, 0.40 mmol). Themixture was stirred at 80° C. for 16 hours. The mixture was concentratedthen diluted with EtOAc (15 mL) and washed with H₂O (15 mL). The organiclayer was dried (Na₂SO₄), filtered and concentrated. The crude productwas purified by silica gel chromatography, eluting with EtOAc/hexane(0-50%) to give 6-bromo-3-(1-(4-chlorophenyl)-2-nitroethyl)-1H-indole(0.175 g, 45.2%). ¹H NMR (CDCl₃, 400 MHz) δ 8.12 (s, 1H), 7.51 (s, 1H),7.28 (d, J=8.5 Hz, 2H), 7.25-7.20 (m, 3H), 7.17 (d, J=8.5 Hz, 1H), 7.15(s, 1H), 5.12 (t, 1H), 5.01 (q, 1H), 4.88 (q, 1H).

Step 2: A solution containing6-bromo-3-(1-(4-chlorophenyl)-2-nitroethyl)-1H-indole (0.210 g, 0.553mmol), bispinacol ester boronate (168 mg, 0.664 mmol) and potassiumacetate (0.163 g, 1.66 mmol) in 1,4-dioxane (5.00 mL) was deoxygenated,and then [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (22.6 mg, 0.0276 mmol, 1:1) was added. Themixture was heated at 80° C. for 15 hours. The mixture was cooled toambient temperature, diluted with H₂O (10 mL) and extracted with EtOAc(2×10 mL). The combined organic were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by silica gelchromatography, eluting with EtOAc/hexane (0-50%) to give pure boronate(0.146 g, 74.5%).(R)-4-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (52.4 mg,0.311 mmol), Bis(triphenylphosphine)palladium(II) chloride (17.5 mg,0.0249 mmol) were added to the boronate (0.146 g, 0.342 mmol), followedby the addition of acetonitrile (0.933 mL) and aqueous KOAc solution(0.933 mL, 1M). The mixture was cooled to ambient temperature, dilutedwith H₂O (10 mL) and extracted with EtOAc (2×10 mL). The combinedorganic were dried (Na₂SO₄), filtered and concentrated. The crudeproduct was purified by silica gel chromatography, eluting withEtOAc/hexane (0-100%) to give(5R)-4-(3-(1-(4-chlorophenyl)-2-nitroethyl)-1H-indol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.115 g, 85.4%). LCMS: M+1 433.4.

Step 3: A suspension of nickel chloride hexahydrate (31.6 mg, 0.133mmol) in methanol (10 mL, 200 mmol) was sonicated until completedissolution. Sodium tetrahydroborate (15.1 mg, 0.398 mmol) was added insmall portion to this stirring solution at room temperature. As more andmore NaBH₄ was added, a precipitate formed. Upon complete addition ofNaBH₄, the suspension was allowed to stir at room temperature for 30minutes. A solution of(5R)-4-(3-(1-(4-chlorophenyl)-2-nitroethyl)-1H-indol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(115 mg, 0.266 mmol) in MeOH (2 mL) was added to this stirringsuspension. Sodium tetrahydroborate (35.2 mg, 0.930 mmol) was carefullyadded in small portions to this stirring suspension. The reactionmixture was stirred for 1 hour at room temperature. The reaction mixturewas filtered thru celite, and the filtrate was treated with aqueousNH₄OH (10 mL, 20% solution NH₄OH). The filtrate was then extracted withCHCl₃ (4×10 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. Crude2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethanaminewas carried to next step. LCMS: M+1 403.5.

Step 4: Acetone (0.0195 mL, 0.266 mmol) was added to a solution of2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethanamine(107 mg, 0.266 mmol) and N,N-diisopropylethylamine (0.139 mL, 0.797mmol) in methylene chloride (2.0 mL). The reaction mixture was stirredfor 10 minutes, and then sodium triacetoxyborohydride (0.0188 g, 0.0885mmol) was added. After stirring for 2.5 hours, saturated NaHCO₃ wasadded, and the mixture was stirred vigorously 10 minutes. The mixturewas extracted with DCM (3×10 mL). The combined organic were dried(Na₂SO₄), filtered and concentrated. The crude product was purified bySFC chiral chromotagraphy (Chiral OJH (21.2×250 mm) 25% methanol+0.1%TEA) to giveN-((R)-2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethyl)propan-2-amine(19.8 mg, 16.8%) as the first peak. LCMS: M+1 445.3. ¹H NMR (CDCl₃, 400MHz) δ 11.16 (s, 1H), 8.93 (s, 1H), 7.93 (s, 1H), 7.49-7.46 (m, 3H),7.38 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 4.36 (t, 1H), 3.89 (m,1H), 3.23 (m, 1H), 3.14-2.99 (m, 2H), 2.94-2.86 (m, 1H), 2.77 (m, 1H),2.34 (m, 1H), 1.68 (m, 1H), 0.96 (d, 6H), 0.92 (d, 3H).

Example 7

(R)-N-(2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl)propan-2-amine

Step 1: 2-Propanamine (1.71 mL, 20.0 mmol) was added to a mixture of2-(4-chlorophenyl)oxirane (2.69 g, 16.7 mmol) and water (6.67 mL). Themixture was stirred at room temperature. After 24 hours, additional2-propanamine (1.13 mL, 13.3 mmol) was added. After a total of 40 hours,water (15 mL) was added. The contents were extracted with ether (4×50mL). The combined ether solutions were dried (Na₂SO₄). After filtrationand evaporation of solvents, the material was dissolved in methylenechloride (100 mL). Di-tert-butyldicarbonate (4.01 g, 18.4 mmol) wasadded, followed by triethylamine (2.56 mL, 18.4 mmol). The mixture wasstirred at room temperature for 20 hours. More Boc₂O (2 g) was added.After 4 hours, imidazole (1.136 g, 16.68 mmol) was added. After 20minutes, the contents were diluted with DCM (50 mL), washed with 1.0MNaH₂PO₄ (2×50 mL), and dried (Na₂SO₄). The crude was purified by flashchromatography to give tert-butyl2-(4-chlorophenyl)-2-hydroxyethyl(isopropyl)carbamate (3.32 g, 63%).

Step 2: (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(137 mg, 0.812 mmol) and 4-hydroxybenzeneboronic acid (123 mg, 0.894mmol) was dissolved in isopropyl alcohol (1.6 mL). Sodium carbonate inwater (0.97 mL, 1.0M) was added slowly, followed bybis(triphenylphosphine)palladium chloride (26.5 mg, 0.0378 mmol). Themixture was stirred at 100° C. (bath) for 16 hours. The contents werediluted with water (5 mL) and EtOAc (10 mL). The aqueous layer wasseparated and extracted with EtOAc (2×5 mL). The combined EtOAcsolutions were washed with brine (5 mL) and dried (Na₂SO₄). The crudewas purified by flash chromatography to give(R)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenol (160mg, 87%) as viscous oil which solidified upon standing.

Step 3: Diethyl azodicarboxylate (0.166 mL, 1.05 mmol) was added slowlyto a solution of tert-butyl2-(4-chlorophenyl)-2-hydroxyethyl(isopropyl)carbamate (265 mg, 0.843mmol), (R)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenol(159 mg, 0.703 mmol), and triphenylphosphine (276 mg, 1.05 mmol) intetrahydrofuran (7.0 mL) at −30° C. (bath). The mixture was allowed towarm up to room temperature and stirred overnight. Most of the startingmaterial remained. Triphenylphosphine (276 mg, 1.05 mmol) was added. Thecontents were cooled at −30° C. Diethyl azodicarboxylate (0.166 mL, 1.05mmol) was added. The mixture was stirred at room temperature for 4hours. tert-Butyl 2-(4-chlorophenyl)-2-hydroxyethyl(isopropyl)carbamate(265 mg, 0.843 mmol) was added. The mixture was stirred at roomtemperature overnight. EtOAC (10 mL) and water (10 mL) were added. Theorganic layer was separated. The aqueous layer was extracted with EtOAc(2×10 mL). The combined organic solutions were dried (Na₂SO₄). The crudewas purified by flash chromatography to give (R)-tert-butyl2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl(isopropyl)carbamate(26 mg, 7%).

Step 4: Trifluoroacetic acid (0.5 mL) was added dropwise to a solutionof (R)-tert-butyl2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl(isopropyl)carbamate(26 mg, 0.0498 mmol) in methylene chloride (1.0 mL) at 0° C. The mixturewas stirred at 0° C. for 10 minutes and then at room temperature for 2hours. The contents were concentrated. The resulting residue waspurified by reverse-phase HPLC to give(R)-N-(2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl)propan-2-amineas TFA salt (7.5 mg, 23%). ¹H NMR (d6-DMSO, 500 MHz) δ□(ppm): 8.9 (s,1H), 8.7 (s, br, 2H), 7.8 (t, 2H), 7.5 (m, 4H), 7.1 (d, 2H), 5.7 (d,1H), 3.8 (m, 1H), 3.4-3.5 (m, 2H), 3.3-3.4 (m, 1H), 3.0-3.1 (m, 1H), 2.9(m, 1H), 2.3 (m, 1H), 1.7 (m, 1H), 1.3 (dd, 6H), 0.9 (dd, 3H). MS(422.3, M+1).

Example 8

(5R,7R)-4-(3-(Amino(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

Step 1: 1,1-Carbonyldiimidazole (1.60 g, 9.89 mmol) was added to asolution of 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetic acid(2.57 g, 9.00 mmol) in CH₂Cl₂ (22.5 mL, 9.00 mmol), and the mixture wasstirred for 30 minutes until gas evolution ceased. Hydrazine (0.367 mL,11.7 mmol) was then added to this solution, and the mixture was stirredat room temperature for 12 hours. The reaction mixture was diluted withCH₂Cl₂ and washed with NaHCO₃ (10%). The organic layer was dried(Na₂SO₄) and concentrated. The residue was purified by reversed-phasechromatography (Biotage SP4, 40+M, C₁₈, 25% to 100% MeCN/H₂O). Fractionscontaining product were poured into a separatory funnel and extractedwith ethyl acetate (3×). The combined organic layers were dried andconcentrated to give tert-butyl1-(4-chlorophenyl)-2-hydrazinyl-2-oxoethylcarbamate as a solid (1.95 g,72%). LCMS (APCI⁺) M+H⁺: 299 (5%); M+H⁺-Boc: 199 (100%); rt=2.78minutes. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.30 (s, 4H), 5.85 (d,J=6.6 Hz, 1H), 5.21 (s, 1H), 3.87 (s, 2H), 1.42 (s, 9H).

Step 2: Triethyloxonium hexafluorophosphate (3.20 g, 28.0 mmol) wasadded to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (2.54 g,12.7 mmol) in CH₂CL₂ (31.7 mL) at 0° C., and the resulting solution wasstirred at room temperature for 18 hours. The reaction mixture waswashed with saturated NaHCO₃, dried (Na₂SO₄), and concentrated to givetert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate as an oil.LCMS (APCI⁺) M+H-t-Bu: 173 (40%); rt=3.14 minutes.

Step 3: A solution of tert-butyl3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate (0.762 g, 3.34 mmol) andtert-butyl 1-(4-chlorophenyl)-2-hydrazinyl-2-oxoethylcarbamate (1.00 g,3.34 mmol) in toluene (6.67 mL, 3.34 mmol) was heated to reflux andstirred at this temperature for 1 hour. The reaction mixture was cooledto room temperature, diluted with ethyl acetate, and washed with water.The organic layer was dried and concentrated to give a residue that waspurified by reverse phase chromatography (Biotage SP4, 40+M, C₁₈, 10% to100% ACN/H₂O) to afford tert-butyl3-((tert-butoxycarbonylamino)(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate(0.92 g, 60%). LCMS (APCI⁺) M+H⁺: 463 (25%), 464 (90%), 466 (25%), 467(5%); rt=3.56 minutes. ¹H NMR (400 MHz, CDCl₃) δ □7.33 (d, J=8.6 Hz,1H), 7.29 (d, J=8.6 Hz, 1H), 6.12 (d, J=7.8 Hz, 1H), 5.87 (d, J=7.8 Hz,1H), 4.84 (d, J=17.6 Hz, 1H), 4.75 (d, J=17.6 Hz, 1H), 3.93 (m, 1H),3.80 (m, 1H), 3.73 (m, 1H), 3.49 (m, 1H), 1.47 (s, 9H), 1.41 (s, 9H).

Step 4: A solution of tert-butyl3-((tert-butoxycarbonylamino)(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate(0.652 g, 1.41 mmol) in MeOH (7.03 mL, 1.41 mmol) was saturated with HCl(g). The reaction mixture was stirred at room temperature for 30 minutesand then concentrated in vacuo to afford(4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanaminebishydrochloride as a foam (0.47 g, 99%). LCMS (APCI⁺) M+H⁺: 264 (50%),266 (10%), 267 (3%); rt=1.76 minutes. ¹H NMR (400 MHz, d₆-DMSO) δ □10.62(s, 1H), 10.18 (s, 1H), 9.43 (s, 3H), 7.57 (d, J=8.6 Hz, 2H), 7.53 (d,J=8.6 Hz, 2H), 6.13 (m, 1H), 4.51 (m, 2H), 4.44 (m, 1H), 3.56 (m, 3H).

Step 5: A solution of(4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanaminebishydrochloride (50 mg, 0.149 mmol),(5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (49.8 mg, 0.149 mmol) and DIEA (0.130 mL, 0.745 mmol) inNMP (0.30 mL, 0.149 mmol) was heated at 100° C. for 1 day. The crudereaction mixture was diluted with methanol and filtered. The filtratewas purified (C18, 5-95% MeCN/H₂O+1% TFA). The fractions containingproduct were isolated by basifying with 25% NaOH and extracting intoCH₂Cl₂/isopropanol (3:1). The organic layers were concentrated, and theresidue was diluted with methanol. The solution was saturated with HCl(g). The solution was evaporated to give(5R,7R)-4-(3-(Amino(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olbishydrochloride (15.3 mg, 25%). LCMS (APCI⁺) rt=2.28 min. ¹H NMR (400MHz, d₆-DMSO+3 drops D₂O) δ 8.83 (d, J=7.8 Hz, 1H), 7.55 (s, 4H), 6.02(d, J=8.6 Hz, 1H), 5.30 (m, 1H), 4.54 (m, 1H), 4.36 (m, 1H), 4.24 (m,1H), 4.09 (m, 1H), 3.48 (m, 1H), 2.21 (m, 1H), 2.08 (m, 1H), 1.26 (m,1H), 1.19 (m, 3H).

Example 9

(5R,7R)-4-(3-(1-(4-Chlorophenyl)-2-(isopropylamino)ethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

Step 1: Using the procedure from Example 8, Step1,3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoicacid (2.00 g, 5.85 mmol) was used to afford tert-butyl2-(4-chlorophenyl)-3-hydrazinyl-3-oxopropyl(isopropyl)carbamate (1.90 g,5.34 mmol, 91%). LCMS (APCI+) M+H⁺: 356 (100%), 358 (50%), rt 3.50minutes.

Step 2: Using the procedure from Example 8, Step 3, tert-butyl2-(4-chlorophenyl)-3-hydrazinyl-3-oxopropyl(isopropyl)carbamate (1.90 g,5.34 mmol) was used to afford tert-butyl3-(2-(tert-butoxycarbonyl(isopropyl)amino)-1-(4-chlorophenyl)ethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate(1.66 g, 3.18 mmol, 60%). LCMS (APCI+) M+H⁺: 519 (66%), 520 (95%), rt4.09 minutes.

Step 3: Using the procedure from Example 8, Step 4, tert-butyl3-(2-(tert-butoxycarbonyl(isopropyl)amino)-1-(4-chlorophenyl)ethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate(1.66 g, 3.18 mmol) was used to affordN-(2-(4-chlorophenyl)-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)ethyl)propan-2-aminebishydrochloride (0.65 g, 1.66 mmol, 52%). LCMS (APCI+) M+H⁺: 320(100%), 322 (25%), rt 1.89 minutes.

Step 4: Using the procedure from Example 8, Step 5,N-(2-(4-chlorophenyl)-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)ethyl)propan-2-aminebishydrochloride (95 mg, 0.15 mmol) was used to afford(5R,7R)-4-(3-(1-(4-chlorophenyl)-2-(isopropylamino)ethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olbishydrochloride (20 mg, 0.042 mmol, 28%). LCMS APCI+(M+H⁺): rt 2.20minutes. HPLC purity at 254 nm 98%, rt=1.82 minutes. ¹H NMR (400 MHz,d₆-DMSO+2 drops D₂O) δ 8.81 (d, J=6.6 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H),7.40 (dd, J=8.6 Hz, 3.5 Hz, 2H), 5.48 (dd, J=29, 16 Hz, 1H), 5.32 (td,J=8.2, 2.0 Hz, 1H), 5.21 (dd, J=32, 17 Hz, 1H), 4.84 (q, J=7 Hz, 1H),4.31 (m, 2H), 3.84 (m, 1H), 3.71 (m, 1H), 3.43 (m, 4H), 2.23 (dd, J=12,8.2 Hz, 1H), 2.12 (m, 1H), 1.26 (d, J=6.6 Hz, 6H), 1.16 (t, J=7.5 Hz,3H).

Example 10

(4-Chlorophenyl)(7-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine

Using the procedure from Example 8, Step 5, using(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine and(4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanaminebishydrochloride (100 mg, 0.30 mmol) to afford(4-chlorophenyl)(7-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanaminebishydrochloride (75 mg, 0.19 mmol, 64%): LCMS APCI+(M+H⁺): 396 (60%),398 (20%), rt 2.48 min. HPLC purity at 254 nm>99%, rt=1.68 min. ¹H NMR(400 MHz, d₆-DMSO) □ 9.51 (s, 3H), 8.85 (d, J=9.4 Hz, 1H), 7.61 (d,J=7.0 Hz, 2H), 7.55 (d, J=7.8 Hz, 2H), 6.08 (br d, J=9.0 Hz, 1H), 5.42(dd, J=26 Hz, 16 Hz, 1H), 5.19 (dd, J=21 Hz, 18 Hz, 1H), 4.55 (m, 1H),4.29 (m, 1H), 3.79 (m, 1H), 3.14 (m, 1H), 2.96 (m, 1H), 2.32 (m, 1H),1.82 (m, 1H), 1.15 (t, J=6.8 Hz, 2H), 1.04 (d, J=6.2 Hz, 3H).

Example 11

(5R,7R)-4-(3-((R)-1-Amino-2-(4-chlorophenyl)ethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

Step 1: Using the procedure from Example 8, Step 1,(R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (3.02g, 10.0 mmol) was used to afford (R)-tert-butyl3-(4-chlorophenyl)-1-hydrazinyl-1-oxopropan-2-ylcarbamate (3.16 g, 10.0mmol, >99%). LCMS APCI+(M+H⁺): 314 (95%), 316 (40%), rt 2.92 minutes.

Step 2: Using the procedure from Example 8, Steps 2 and 3,(R)-tert-butyl 3-(4-chlorophenyl)-1-hydrazinyl-1-oxopropan-2-ylcarbamate(3.16 g, 10.0 mmol) was used to afford (R)-tert-butyl3-(1-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)ethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate(4.03 g, 8.43 mmol, 84%). LCMS APCI+(M+H⁺): 477 (20%), 478 (80%), 479(20%), rt 3.63 minutes.

Step 3: Using the procedure from Example 8, Step 4, (R)-tert-butyl3-(1-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)ethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate(4.03 g, 8.43 mmol) was used to afford(R)-2-(4-chlorophenyl)-1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)ethanaminebishydrochloride (2.47 g, 7.06 mmol, 84%). LCMS APCI+(M+H⁺): 278 (100%),rt 1.91 minutes. ¹H NMR (400 MHz, d₆-DMSO) δ 10.57 (br s, 1H), 10.43 (brs, 1H), 9.05 (br s, 3H), 7.33 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H),4.95 (br s, 1H), 4.52 (m, 3H), 3.92 (m, 1H), 3.51 (m, 2H), 3.38 (m, 2H).

Step 4: Using the procedure from Example 8, Step 5,(R)-2-(4-chlorophenyl)-1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)ethanaminebishydrochloride (66 mg, 0.114 mmol) was used to afford(5R,7R)-4-(3-((R)-1-amino-2-(4-chlorophenyl)ethyl)-5,6-dihydro-[1,2,4]triazolopyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olhydrochloride (49 mg, 0.046 mmol, 40%). LCMS APCI+(M+H⁺): 426 (100%),428 (20%), rt 2.17 minutes. HPLC purity at 254 nm>99%, rt=1.73 minutes.¹H NMR (400 MHz, d₆-DMSO) δ 8.98 (s, 3H), 8.85 (s, 1H), 7.30 (d, J=7.8Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 5.30 (m, 1H), 5.23 (s, 2H), 4.85 (br s,1H), 4.35 (m, 1H), 4.00 (m, 1H), 3.76 (m, 1H), 3.70 (s, 1H), 3.61 (s,1H), 3.51 (m, 1H), 3.40 (m, 1H), 3.27 (m, 1H), 2.16 (m, 2H), 1.15 (d,J=7.0 Hz, 3H).

Example 12

(5R,7R)-4-(4-(1-(4-Chlorophenyl)-2-(isopropylamino)ethylamino)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olhydrochloride

Step 1: TMSCN (19.9 mL, 149 mmol) was added to a solution of4-chlorobenzaldehyde (20.0 g, 142 mmol), 4-bromoaniline (25.1 g, 146mmol), and sulfamic acid (0.691 g, 7.11 mmol) in MeOH (56.9 mL), and thereaction mixture was stirred at room temperature for 6 hours. Thereaction mixture was filtered, and the filter cake was washed withethanol, affording 2-(4-bromophenylamino)-2-(4-chlorophenyl)acetonitrileas a solid (38.0 g, 83%). ¹H NMR (400 MHz, d₆-DMSO) δ □7.53 (d, J=8.2Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 6.64 (d, J=9.0Hz, 2H), 5.38 (d, J=9.0 Hz, 1H), 4.06 (d, J=9.0 Hz, 1H).

Step 2: Lithium aluminum hydride (52.9 mL, 52.9 mmol) in THF (1.0M) wasadded to a solution of2-(4-bromophenylamino)-2-(4-chlorophenyl)acetonitrile (20.0 g, 62.2mmol) in THF (311 mL, 62.2 mmol) at −78° C. The reaction was allowed tostir at −78° C. and gradually warmed to room temperature over 4 hours.The reaction mixture was poured into 1N HCl. The solution was thenbasified and extracted with ethyl acetate (3×). The combined organiclayers were washed with brine, dried and concentrated to give an oil.This residue was purified by column chromatography, eluting first withethyl acetate/hexanes (2:1) then 5% MeOH/CH₂Cl₂->10% MeOH/CH₂Cl₂+1%NH₄OH, affording N1-(4-bromophenyl)-1-(4-chlorophenyl)ethane-1,2-diamineas an oil (9.60 g, 49%). ¹H NMR (400 MHz, CD₃OD) δ □7.38 (d, 2H), 7.34(d, 2H), 7.15 (d, 2H), 6.53 (d, 2H), 4.59 (dd, J=9.8, 4.7 Hz, 1H), 3.14(dd, J=12.9, 4.7 Hz, 1H), 3.05 (dd, J=12.9, 9.4 Hz, 1H).

Step 3: NaBH(OAc)₃ (4.88 g, 23.0 mmol) was added to a solution ofN1-(4-bromophenyl)-1-(4-chlorophenyl)ethane-1,2-diamine (5.00 g, 15.4mmol) and propan-2-one (1.24 mL, 16.9 mmol) in 1,2-dichloroethane (51.2mL, 15.4 mmol), and the resulting solution was stirred at roomtemperature for 12 hours. The reaction was followed by LCMS. Thereaction mixture was quenched with saturated NaHCO₃ and extracted withethyl acetate (3 X). The combined organic layers were dried andconcentrated to give the desired product as an oil, which was notfurther purified (5.40 g, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J=9.0Hz, 2H), 7.34 (d, J=9.0 Hz, 2H), 7.15 (d, J=9.0 Hz, 2H), 6.53 (d, J=9.0Hz, 2H), 4.59 (m, 1H), 3.10 (m, 2H).

Step 4: A mixture ofN1-(4-bromophenyl)-1-(4-chlorophenyl)-N-2-isopropylethane-1,2-diamine(0.556 g, 1.51 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.576 g,2.27 mmol), KOAc (0.594 g, 6.05 mmol) and DMSO (7.56 mL, 1.51 mmol) wasdegassed with nitrogen for 5 minutes. PdCl₂(dppf)*CH₂Cl₂ (0.062 g, 0.076mmol) was then added to this solution, and the reaction was heated at80° C. overnight under nitrogen. After 1 day, additional4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.15 g,4.54 mmol), KOAc (1.19 g, 12.1 mmol) and PdCl₂(dppf)*CH₂Cl₂ (0.124 g,0.152 mmol) was added, and the reaction was heated at 80° C. for anadditional 24 hours. The reaction mixture was diluted with ethyl acetateto precipitate inorganic salts. The slurry was filtered to remove thesalts, and the filtrate was concentrated and loaded directly onto a C₁₈samplet (40+M) and eluted on a Biotage Horizon (10%-100% ACN/H₂O+1% iPA,1 mM NH₄OAc). The column fractions containing product were poured into aseparatory funnel, basified with 1N NaOH and extracted with ethylacetate. The combined organic layers were dried with sodium sulfate andconcentrated to afford the product as a foam (0.220 g, 35%). LCMSAPCI+(M+H⁺): 415 (25%), 417 (10%), rt 3.76 minutes.

Step 5:1-(4-Chlorophenyl)-N2-isopropyl-N-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1,2-diamine(0.075 g, 0.181 mmol), Pd(PPh₃)₄ (0.017 g, 0.015 mmol), and 2N Na₂CO₃(0.226 mL, 0.452 mmol) were added to a solution of(5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (0.050 g, 0.151 mmol) in n-propanol (0.464 mL, 0.151mmol). The suspension was degassed by bubbling nitrogen through thesolution. The dark suspension was heated at 90° C. for 14 hours. Themixture was cooled to room temperature and then concentrated. Theresulting residue was diluted with ethyl acetate and filtered. Thefiltrate was washed with saturated NaHCO₃ and brine. The organic layerwas dried and concentrated. The resulting residue was purified byBiotage SP4 (C₁₈, 25+0-100% ACN). The product-containing fractions werecollected and repurified by Gilson C₁₈ (5-95 ACN/H₂O+1% TFA). Tubescontaining product were identified by LCMS, collected and evaporated.The material was partially dissolved in CH₂Cl₂, and HCl (g) was bubbledthrough the mixture to precipitate solid(5R,7R)-4-(4-(1-(4-chlorophenyl)-2-(isopropylamino)ethylamino)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olhydrochloride (8.10 mg, 12%). LCMS APCI+(M+H⁺): 437 (100%), 439 (30%),rt 2.55 minutes. HPLC purity at 254 nm>99%, rt=2.17 minutes. ¹H NMR (400MHz, d₆-acetone) δ 8.88 (s, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.6Hz, 1H), 7.59 (d, J=3.5 Hz, 1H), 7.58 (d, J=3.1 Hz, 1H), 7.40 (d, J=8.2Hz, 2H), 6.65 (t, J=9.0 Hz, 2H), 5.26 (m, 1H), 5.15 (td, J=7.4, 4.3 Hz,1H), 3.88 (m, 2H), 3.62 (br s, 2H), 3.50 (br s, 1H), 2.17 (m, 2H), 1.45(m, 2H), 1.41 (d, J=6.6 Hz, 6H), 1.10 (t, J=7.0 Hz, 3H), 0.88 (m, 1H).

Example 13

(R)-N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide

Step 1: A solution of Na₂CO₃ (1.65 mL, 1M) was added to a solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (253 mg,1.50 mmol) and 4-methoxycarbonylphenylboronic acid (297 mg, 1.65 mmol)in 1,4-dioxane (4.5 mL). The mixture was sparged with N₂ for 2 minutes.The catalyst Pd(dppf)Cl₂ (98 mg, 0.12 mmol) was added in one portion.The reaction vial was sealed and heated in microwave to 110° C. for 30minutes. Water (20 mL) was added to the mixture and extracted with DCM(3×15 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by flash chromatography(0-50% EtOAc/hexane gradient elution) to give (R)-methyl4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoate as anoil (300 mg, 70%). ¹H NMR (CDCl₃, 500 MHz) δ 9.07 (s, 1H), 8.16 (d, =8.5Hz, 2H), 7.88 (d, J=8.5 Hz, 2H), 3.96 (s, 3H), 3.81-3.76 (m, 1H),3.15-3.00 (m, 2H), 2.44-2.40 (m, 1H), 1.78-1.74 (m, 1H), 1.01 (d, J=6.5Hz, 3H).

Step 2: A solution of LiOH (64 mg, 2.68 mmol) in H₂O (10 mL) was addedto a solution of (R)-methyl4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoate (359 mg,1.34 mmol) in THF (6 mL) at 0° C. The mixture was allowed to warm up toroom temperature and stirred overnight. The volatile solvent was removedin vacuo. The aqueous layer was acidified with 1N HCl to a pH of 3. Asolid precipitated, and was collected by filtration, washed with ether,and dried in vacuo to give(R)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acidas a solid (306 mg, 90%).

Step 3: DIPEA (37 μL, 0.21 mmol) andO-(benzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(80 mg, 0.21 mmol) were added to a solution of(R)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid(51 mg, 0.2 mmol) in DMF (1 mL). The mixture was heated to 70° C. for 18hours. The mixture was diluted with DCM (10 mL). Saturated NH₄Cl (10 mL)was added. The layers were separated. The aqueous layer was extractedwith DCM (2×10 mL). The combined organics were dried (Na₂SO₄), filteredand concentrated. The crude product was purified by flash chromatography(0-100% EtOAc/hexane gradient elution) to give (R)-tert-butyl2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamido)ethylcarbamateas an oil (49 mg, 31%).

Step 4: TFA (182 μL, 2.36 mmol) was added to a solution of(R)-tert-butyl2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamido)ethylcarbamate(49 mg, 0.094 mmol) in DCM (1 mL). The mixture was stirred at roomtemperature for 1.5 hours. The mixture was concentrated in vacuo. Thecrude product was purified by reverse phase HPLC to give(R)-N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamideas an oil (9 mg, 22%). MS (APCI+) [M+H]⁺421.2. ¹H NMR (D₂O, 500 MHz) δ9.09 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.35 (d,J=8.5 Hz, 2H), 7.15 (D, J=8.0 Hz, 2H), 4.63 (s, 2H), 3.87 (t, J=6.5 Hz,2H), 3.82-3.79 (m, 1H), 3.26-3.11 (m, 4H), 2.63 (s, 2H), 2.50-2.42 (m,1H), 1.86-1.81 (m, 1H), 0.86 (s, J=7.00 Hz, 3H).

Example 14

(R)-N-(2-aminoethyl)-N-(4-trifluoromethylbenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide

(R)-N-(2-Aminoethyl)-N-(4-trifluoromethylbenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamidewas prepared in a similar manner as(R)-N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide.MS (APCI+) [M+H]⁺455.2. ¹H NMR (D₂O, 500 MHz) δ 8.86 (s, 1H), 7.77-7.96(m, 4H), 7.56 (d, J=8.0 Hz, 2H0, 7.35 (d, J=8.0 Hz, 2H), 4.75 (s, 2H),3.84 (t, J=6.0 Hz, 2H), 3.70-3.67 (m, 1H), 3.84 (t, J=6.0 Hz, 2H),3.24-2.87 (m, 2H), 2.41-2.35 (m, 1H), 1.76-1.71 (m, 1H), 1.27-1.19 (m,1H), 0.81 (d, J=7.0 Hz, 3H).

Example 15

(R)-N-(2-aminoethyl)-N-(4-bromolbenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide

(R)-N-(2-Aminoethyl)-N-(4-bromolbenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamidewas prepared in a similar manner as(R)-N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide.MS (APCI+) [M+H]⁺465.2. ¹H NMR (D₂O, 500 MHz) δ 8.82 (s, 1H), 7.68 (d,J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.0 Hz, 7.06 (d, J=8.0Hz, 2H), 4.58 (s, 2H), 3.75 (t, J=6.5 Hz, 2H), 3.69-3.66 (m 1H),3.22-2.78 (m, 4H), 2.37-2.29 (m, 1H), 1.71-1.67 (m, 1H), 1.22-1.37 (m,2H), 0.75 (d, J=6.0 Hz, 3H).

Example 16

(S)-2-(4-bromophenyl)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropiperidin-1(2H)-yl)propan-1-one

Step 1: A solution of Na₂CO₃ (2 mL, 2M) was added to a solution of(5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (334 mg, 1.00 mmol),3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid, pinacolester (340 mg, 1.10 mmol) in 1,4-dioxane (6 mL). The mixture was spargedwith N₂ for 2 minutes. The catalyst Pd(dppf)Cl₂ (65 mg, 0.08 mmol) wasadded in one portion. The reaction vial was sealed and heated inmicrowave to 120° C. for 20 minutes. A solution of LiOH (0.7 mL, 3M) wasadded. The mixture was stirred at room temperature for 18 hours. Water(30 mL) was added to the mixture, extracted with DCM (3×20 mL). Thecombined organics were dried (Na₂SO₄), filtered and concentrated. Thecrude product was purified by flash chromatography (0-5% MeOH/DCMgradient elution) to give tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylateas an oil (221 mg, 67%). ¹H NMR (CDCl₃, 400 MHz) δ 9.01 (s, 1H), 6.44(s, 1H), 5.30 (m, 1H), 4.16-4.11 (m, 2H), 3.71-3.55 (m, 3H), 2.83-2.78(m, 1H), 2.50-2.30 (m, 1H), 2.28-2.24 (m, 2H), 1.50 (s, 9H), 1.28-1.22(m, 3H).

Step 2: TFA (193 μL, 2.5 mmol) was added to a solution of tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(33 mg, 0.10 mmol) in DCM (1 mL). The mixture was stirred at roomtemperature for 1 hour, and concentrated to give(5R,7R)-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olas an oil, which was used further without purification.

Step 3: DIPEA (174 μL, 1.0 mmol) andO-(benzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(42 mg, 0.11 mmol) were added to a solution of(5R,7R)-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol(23 mg, 0.10 mmol) and(S)-2-(4-bromophenyl)-3-(tert-butylamino)propanoic acid (33 mg, 0.11mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1hour. The reaction was quenched with saturated NH₄Cl, extracted with DCM(2×10 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by reverse phase HPLC togive(S)-2-(4-bromophenyl)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropiperidin-1(2H)-yl)propan-1-oneditrifluoroacetic acid as a solid (13 mg, 24%). MS (APCI+) [M+H]⁺514.2.¹H NMR (D₂O, 400 MHz) 8.66 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.10 (J=8.4Hz, 2H), 6.18-6.15 (m, 1H), 5.06-5.00 (m, 1H), 4.44-4.40 (m, 1H),4.25-4.22 (m, 1H), 4.01-3.65 (m, 5H), 3.52-3.45 (m, 2H), 3.38-3.05 (m,3H), 2.05-1.82 (m, 3H), 1.17 (s, 9H), 0.77 (d, J=7.2 Hz, 3H).

Example 17

(S)-2-(4-bromophenyl)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)propan-1-one

Step 1: 5% Pd/C (10 mg) was added to a solution of tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(17 mg, 0.05 mmol) in EtOAc (1 mL). The mixture was stirred at roomtemperature under a hydrogen atmosphere overnight. The mixture wasfiltered through celite and concentrated to give tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylateas an oil (13 mg, 78%), which was used further without purification.

Step 2: TFA (77 μL, 1.0 mmol) was added to a solution of tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylate(13 mg, 0.04 mmol) in DCM (1 mL). The mixture was stirred at roomtemperature for 1 hour and concentrated to give(5R,7R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olas an oil, which was used further without purification.

Step 3: DIPEA (70 μL, 0.40 mmol) andO-(benzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(16 mg, 0.042 mmol) were added to a solution of(5R,7R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol(9.3 mg, 0.04 mmol) and(S)-2-(4-bromophenyl)-3-(tert-butylamino)propanoic acid (12 mg, 0.4mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1hour. The reaction was quenched with sat. NH₄Cl and extracted with DCM(2×10 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by reverse phase HPLC togive(S)-2-(4-bromophenyl)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)propan-1-oneditrifluoroacetic acid as a solid (4.6 mg, 22%). MS (APCI+) [M+H]⁺516.2.¹H NMR (D₂O, 500 MHz) δ 8.85 (s, 1H), 7.68 (d, J=7.5 Hz, 2H), 7.34 (d,J=7.5 Hz, 2H), 5.33 (t, J=4.5 Hz, 1H), 4.64-4.59 (m, 1H), 4.38-4.34 (m,1H), 3.97-3.89 (m, 1H), 3.70-3.47 (m, 2H), 3.38-3.13 (m, 3H), 2.91-2.82(m, 2H), 2.35-2.29 (m, 1H), 2.14-2.07 (m, 1H), 1.94-1.77 (m, 2H),1.58-1.47 (m, 1H), 1.40 (s, 9H), 1.18 (d, J=7.0 Hz, 3H).

Example 18

(S)-2-(4-chlorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)ethanone

Step 1: A solution of Na₂CO₃ (0.36 mL, 2M) was added to a solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (101 mg,0.60 mmol), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronicacid, pinacol ester (204 mg, 0.66 mmol) in 1,4-dioxane (1.8 mL). Themixture was sparged with N₂ for 2 minutes. The catalyst Pd(PPh₃)₂Cl₂ (21mg, 0.03 mmol) was added in one portion. The mixture was heated at 110°C. under N₂ for 8 hours. Water (20 mL) was added to the mixture andextracted with DCM (3×15 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude product was purified by flashchromatography (first with 0-50% EtOAc/hexane, then with 0-4% MeOH/DCMgradient elution) to give (R)-tert-butyl4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylateas an oil (127 mg, 67%). ¹H NMR (CDCl₃, 500 MHz) δ 8.91 (s, 1H), 6.31(s, 1H), 3.64-3.55 (m, 1H), 3.10-3.03 (m, 2H), 2.98-2.90 (m, 2H),2.83-2.78 (m, 1H), 2.42-2.34 (m, 2H), 1.77-1.69 (m, 2H). 1.49 (s, 9H),1.19 (d, J=7.0 Hz, 3H).

Step 2: 5% Pd/C (40 mg) was added to a solution of (R)-tert-butyl4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(63 mg, 0.20 mmol) in EtOAc (4 mL). The mixture was stirred at roomtemperature under a hydrogen atmosphere overnight. The mixture wasfiltered through celite and concentrated to give (R)-tert-butyl4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylateas an oil (58 mg, 91%), which was used further without purification.

Step 3: TFA (193 μL, 2.50 mmol) was added to a solution of(R)-tert-butyl4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylate(32 mg, 0.10 mmol) in DCM (1 mL). The mixture was stirred at roomtemperature for 1 hour and concentrated to give(R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidineas an oil, which was used further without purification.

Step 4: DIPEA (174 μL, 1.00 mmol) andO-(benzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(25 mg, 0.065 mmol) were added to a solution of(R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(22 mg, 0.10 mmol) and(S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chlorophenyl)aceticacid (20 mg, 0.054 mmol) in DCM (2 mL). The mixture was stirred at roomtemperature for 2 hours. The reaction was quenched with saturated NH₄Cland extracted with DCM (2×10 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude product was purified byflash chromatography (0-5% MeOH/DCM gradient elution) to give(S)-tert-butyl5-((S)-1-(4-chlorophenyl)-2-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylateas a solid (26 mg, 84%). ¹H NMR. (CD₃OD, 500 MHz) δ 8.73 (s, 3H), 7.42(d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 4.73-4.70 (m, 2H), 4.40-4.35(m, 1H), 3.89-3.86 (m, 1H), 3.76-3.70 (m, 2H), 3.49-3.43 (m, 1H),3.25-3.20 (m, 2H), 3.18-2.97 (m, 2H), 2.86-2.70 (m, 3H), 2.34-2.25 (m,1H), 2.16-2.13 (m, 1H), 1.83-1.67 (m, 2H), 1.54 (s, 9H), 1.38 (s, 3H),1.36 (s, 3H), 1.25-1.20 (m, 3H).

Step 5: A solution of 4M HCl in 1,4-dioxane (0.344 mL) was added to asolution of (S)-tert-butyl5-((S)-1-(4-chlorophenyl)-2-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate(26 mg, 0.046 mmol) in 1,4-dioxane (1 mL) at 0° C. The mixture wasallowed to warm up and stirred at room temperature for 4 hours. Themixture was concentrated in vacuo. The resulting residue was dissolvedin minimal DCM and added to the ether (5 mL) at 0° C. A solidprecipitated. The mixture was decanted and dried in vacuo to give(S)-2-(4-chlorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)ethanonedihydrochloride as a solid (26 mg, 100%). MS (APCI+) [M+H]⁺467.3. ¹H NMR(D₂O, 500 MHz) δ 8.96 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5Hz, 2H), 4.60-4.20 (m, 3H), 4.01-3.52 (m, 6H), 3.48-3.05 (m, 4H),2.85-2.82 (m, 1H), 2.43-2.36 (m, 1H), 1.96-1.86 (m, 5H), 1.32 (s, 3H),1.1.31 (s, 3H), 1.19 (d, J=7.5 Hz, 3H).

Example 19

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-3-(isopropylamino)propan-1-one

Step 1:(5R,7R)-4-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (65 mg, 0.195 mmol) was dissolved in i-PrOH (5 mL), andthen tert-butyl 1,4-diazepane-1-carboxylate (51 mg, 0.253 mmol) wasadded. N,N-Diisopropylethylamine (49 mg, 0.350 mmol) was added, and thereaction mixture was heated to 80° C. for 12 hours, after which thesolvents were removed under reduced pressure. The resulting residue wastaken up into EtOAc and then washed twice with water and once withbrine. The organic portion was dried over magnesium sulfate, filtered,and then concentrated. The resulting residue was purified via silica gelchromatography to give tert-butyl4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azepane-1-carboxylate(78 mg, 81%). LCMS (APCI+) M+=498.1, Rt=3.81 min.

Step 2: tert-Butyl4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azepane-1-carboxylate(78 mg, 0.160 mmol) was dissolved in dichloromethane (2 mL) and then HCl(4M in dioxane, 0.58 mL) was added. The resulting mixture was stirred atambient for 4 hours, at which time it was concentrated via rotaryevaporation. The resulting(5R,7R)-4-(1,4-diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate hydrochloride (64 mg, 94%) was used without furtherpurification. LCMS (APCI+) M+H+=398.1, Rt=2.32 min.

Step 3:(5R,7R)-4-(1,4-Diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate hydrochloride (61 mg, 0.140 mmol) and3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid(48 mg, 0.140 mmol) were suspended in dichloromethane (5 mL).N,N-Diisopropylethylamine (54 mg, 0.420 mmol) was then added. HBTU (53mg, 0.140 mmol) was added, and the resultant solution was stirred atambient for 16 hours. After this time, the reaction mixture was quenchedby the addition of saturated sodium carbonate solution and thenextracted twice with dichloromethane. The combined organic portions weredried over sodium sulfate, filtered, and concentrated. The residue thusobtained was purified by silica gel chromatography to give(5R,7R)-4-(4-((S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoyl)-1,4-diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (50 mg, 50%). LCMS (APCI+) M+=721.1, Rt=4.51 min.

Step 4:(5R,7R)-4-(4-((S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoyl)-1,4-diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (50 mg, 0.069 mmol) was dissolved in a THF/water mixture(1:1, 2 mL), and then solid lithium hydroxide (6 mg, 0.139 mmol) wasadded. The resultant mixture was stirred at ambient for 16 hours, atwhich time it was diluted with EtOAc and then washed twice withsaturated sodium bicarbonate solution. The organic layer was dried overmagnesium sulfate, filtered and concentrated. The resulting residue wastaken up in dichloromethane (5 mL), and then HCl (4M in dioxane, 0.25mL) was added. The mixture was stirred for 16 hours, at which timesolvents were removed via rotary evaporation. The resulting residue wasdissolved in dichloromethane (1 mL) and then added to diethyl ether (50mL). The resulting precipitate was collected by filtration and dried togive(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-3-(isopropylamino)propan-1-onedihydrochloride (29 mg, 78%). LCMS (APCI+) M+=472.2, Rt=2.05 min.

Example 20

(5R,7R)-4-(3-(1-(4-chlorophenyl)-2-(isopropylamino)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

Step 1: Oxalyl chloride (3.7 mL, 42 mmol) was added dropwise to asolution of 3-bromothiophenol (5.00 g, 26.4 mmol) in ether (20 mL). Themixture was heated at reflux for 1.5 hours, cooled to room temperature,and concentrated in vacuo. The resulting residue was taken up in DCM (50mL) and cooled to 0° C. Aluminum chloride (4.23 g, 31.7 mmol) was addedin portions. The resultant mixture was stirred at reflux for 30 minutes,cooled to room temperature and poured into ice water with stirring. Theorganic layer was separated and successively washed with saturatedaqueous NaHCO₃, water and brine. The organic layer was dried andconcentrated in vacuo to give a solid, which was suspended in 20% EtOAcin hexanes (50 mL) and heated at reflux for 10 minutes. After cooling,the precipitated solid was collected by filtration to afford crude6-bromobenzo[b]thiophene-2,3-dione (3.22 g, 50%). The6-bromobenzo[b]thiophene-2,3-dione was added to ammonium hydroxide (35%aqueous solution, 40 mL) at 5-10° C., followed by dropwise addition ofhydrogen peroxide (35% aqueous solution, 5.5 mL, 66 mmol). The resultingmixture was stirred at room temperature for 30 minutes, and thenfiltered to give 6-bromobenzo[b]thiophene-3-carboxamide (1.30 g, 38%) asa solid. ¹H NMR (DMSO-d₆, 400 MHz) δ □8.66 (d, J=8.8 Hz, 1H), 8.62 (s,1H), 8.23 (s, 1H), 7.81 (s, 1H), 7.73 (d, J=8.8 Hz, 1H).

Step 2: 10N NaOH solution (10 mL, 100 mmol) was added to a solution of6-bromobenzo[b]thiophene-3-carboxamide (1.20 g, 4.67 mmol) in MeOH (80mL). The mixture was heated at reflux overnight. After cooling, themixture was acidified with 2N HCl. The resulting precipitate wasfiltered and dried to give 6-bromobenzo[d]isothiazole-3-carboxylic acid(1.10 g, 91%) as a solid. ¹H NMR (DMSO-d₆, 400 MHz) δ □8.65 (s, 1H),8.55 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H).

Step 3: DIEA (11.7 mL, 67.4 mmol) and HBTU (7.03 g, 18.5 mmol) wereadded to a solution of 6-bromobenzo[d]isothiazole-3-carboxylic acid(4.35 g, 16.9 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.14 g,21.9 mmol) in DMF (100 mL). The reaction was stirred at room temperaturefor 2 hours. The mixture was partitioned between water and EtOAc. Theorganic layer was washed with aqueous NaHCO₃ solution and brine, driedand concentrated. The residue was purified by column chromatography(hexane:EtOAc, 3:1) to give6-bromo-N-methoxy-N-methylbenzo[d]isothiazole-3-carboxamide (4.60 g,91%) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ □8.12 (m, 2H), 8.59 (d, J=8.8Hz, 1H), 3.83 (s, 3H), 3.49 (s, 3H).

Step 4: 4-Chlorophenyl magnesium bromide (1.0N in THF, 16 mL, 16 mmol)was added to a stirred solution of6-bromo-N-methoxy-N-methylbenzo[d]isothiazole-3-carboxamide (3.5 g, 12mmol) in THF (100 mL). The reaction mixture was stirred at 0° C. for 1hour. The reaction was poured into 1N HCl and extracted into ether. Thecombined organic layers were washed with brine, dried and concentrated.The crude product was suspended in ether and stirred for 15 minutes. Thesolid was collected by filtration to give(6-bromobenzo[d]isothiazol-3-yl)(4-chlorophenyl)methanone (3.3 g, 81%).¹H NMR (CDCl₃, 400 MHz) δ □8.60 (d, J=8.8 Hz, 1H), 8.23 (d, J=8.4 Hz,2H), 8.19 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H).

Step 5: A mixture of NaH (60% mineral oil dispersion, 0.060 g, 1.5 mmol)and DMSO (3 mL) was stirred at 70° C. for 45 minutes. The solution wasthen cooled with cold water, and methyltriphenylphosphonium bromide(0.58 g, 1.6 mmol) in DMSO (3 mL) was added dropwise. Stirring wascontinued for 15 minutes.6-Bromobenzo[d]isothiazol-3-yl)(4-chlorophenyl)methanone (0.300 g, 0.850mmol) was then added in a single portion. The mixture was stirred atroom temperature for 1.5 hours and then poured into ice-water. Themixture was extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The resulting residue waspurified by column chromatography (hexane:DCM, 10:1 to 6:1) to give6-bromo-3-(1-(4-chlorophenyl)vinyl)benzo[d]isothiazole (0.26 g, 87%) asa solid. ¹H NMR (CDCl₃, 400 MHz) δ □8.22 (d, J=8.8 Hz, 1H), 8.12 (s,1H), 7.51 (d, J=8.8 Hz, 1H), 7.30 (m, 4H), 5.97 (s, 1H), 5.81 (s, 1H).

Step 6: A mixture of6-bromo-3-(1-(4-chlorophenyl)vinyl)benzo[d]isothiazole (600 mg, 1.71mmol), DMF (3 mL) and allylamine (3 mL) was stirred at room temperaturefor 3 days. The reaction was partitioned between EtOAc and water. Theorganic phase was washed with brine, dried and concentrated. The residuewas purified by column chromatography (DCM:MeOH, 20:1) to giveN-(2-(6-bromobenzo[d]isothiazol-3-yl)-2-(4-chlorophenyl)ethyl)prop-2-en-1-amine(464 mg, 66%). ¹H NMR (CDCl₃, 400 MHz) δ □8.06 (d, J=1.6 Hz, 1H), 7.59(d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8 Hz, J=1.6 Hz, 1H), 7.25 (m, 4H), 5.86(m, 1H), 5.16 (dd, J=17.2 Hz, J=1.6 Hz, 1H), 5.08 (d, J=10.4 Hz, 1H),4.72 (t, J=7.2 Hz, 1H), 3.62 (dd, J=12.0 Hz, J=8.0 Hz, 1H), 3.31 (m,2H), 3.20 (dd, J=12.0 Hz, J=6.8 Hz, 1H).

Step 7: A mixture ofN-(2-(6-bromobenzo[d]isothiazol-3-yl)-2-(4-chlorophenyl)ethyl)prop-2-en-1-amine(0.441 g, 1.08 mmol), 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(0.507 g, 3.24 mmol), Pd(PPh₃)₄ (0.013 g, 0.011 mmol) and DCM (4 mL) washeated at 35° C. under N₂ for 4 hours. After cooling, DCM wasevaporated. The resulting residue was taken up in ether, washed withsaturated NaHCO₃ and brine, dried and concentrated. The crude productwas dissovled in THF (8 mL). Boc₂O (0.28 g, 1.3 mmol) and Et₃N (0.23 mL,1.6 mmol) were added. The mixture was stirred at room temperature for 1hour. The solvent was evaporated, and the residue partitioned betweenEtOAc and water. The organic phase was separated and washed with brine,dried and concentrated. The resulting residue was purified by columnchromatography (hexanes:EtOAc, 6:1) to give tert-butyl2-(6-bromobenzo[d]isothiazol-3-yl)-2-(4-chlorophenyl)ethylcarbamate(0.39 g, 77%) as a solid. LCMS (APCI+) m/z 467, 469 [M+H]+; Rt=3.71 min.

Step 8: Bis(pinacolato)diboron (0.25 g, 1.0 mmol), tert-butyl2-(6-bromobenzo[d]isothiazol-3-yl)-2-(4-chlorophenyl)ethylcarbamate(0.39 g, 0.83 mmol) and potassium acetate (0.25 g, 2.5 mmol) were addedto DMF (4 mL). The reaction solution was deoxygenated and thendichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane adduct (34 mg, 0.042 mmol) was added. The mixture washeated to 80° C. for 4 hours. The mixture was cooled to room temperatureand partitioned between EtOAc and water. The aqueous phase was extractedwith EtOAc. The combined organic layers were washed with brine, driedand concentrated. The resulting residue was purified by columnchromatography (hexanes:EtOAc, 8:1) to give tert-butyl2-(4-chlorophenyl)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isothiazol-3-yl)ethylcarbamate(0.36 g, 84%) as a solid. LCMS (APCI+) m/z 515, 517 [M+H]+; Rt=4.96 min.

Step 9: DMF (3 mL) and 2M aqueous Na₂CO₃ (0.38 mL, 0.76 mmol) were addedto a nitrogen flushed flask containing tert-butyl2-(4-chlorophenyl)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isothiazol-3-yl)ethylcarbamate(150 mg, 0.291 mmol),(5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (117 mg, 0.350 mmol) anddichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane adduct (12 mg, 0.015 mmol). The mixture was heated at80° C. for 1 hour. The mixture was cooled to room temperature andpartitioned between EtOAc and water. The combined organic layers werewashed with saturated aqueous NaHCO₃ and brine, dried and concentrated.The residue was purified by flash chromatography on silica gel, elutingwith hexanes:EtOAc (4:1 to 1:1) to give(5R,7R)-4-(3-(2-(tert-butoxycarbonylamino)-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (102 mg, 51%) as an oil. LCMS (APCI+) m/z 630, 632[M+H]+; Rt=4.68 min.

Step 10:1 N LiOH aqueous solution (0.30 mL, 0.30 mmol) was added to astirred solution of(5R,7R)-4-(3-(2-(tert-butoxycarbonylamino)-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl4-nitrobenzoate (102 mg, 0.149 mmol) in THF (3 mL). The reaction mixturewas stirred at room temperature overnight. The solvent was evaporated.The resulting residue was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The resulting residue waspurified by column chromatography (DCM:MeOH, 60:1) to give tert-butyl2-(4-chlorophenyl)-2-(6-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]isothiazol-3-yl)ethylcarbamate(62 mg, 78%) as an oil. LCMS (APCI+) m/z 537, 539 [M+H]+; Rt=3.99 min.

Step 11: A solution of tert-butyl2-(4-chlorophenyl)-2-(6-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]isothiazol-3-yl)ethylcarbamate(41 mg, 0.076 mmol) in DCM was treated with 4N HCl in dioxane (0.5 mL).The reaction was stirred at room temperature overnight. The reaction wasconcentrated and triturated with ether (twice) to yield(5R,7R)-4-(3-(2-amino-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oltrihydrochloride (32 mg, 77%). LCMS (APCI+) m/z 437, 439 [M+H]+; Rt=2.48min.

Step 12: DIEA (0.035 mL, 0.20 mmol) was added to a stirred suspension of(5R,7R)-4-(3-(2-amino-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oltrihydrochloride (22 mg, 0.050 mmol) in DCE (1.5 mL). The suspension wasshaken until dissolved. A solution of acetone (0.022 mL, 0.30 mmol) inTHF (0.3 mL) was added. The reaction was allowed to stir at roomtemperature for 15 minutes, at which point Na(OAc)₃BH (27 mg, 0.13 mmol)was added. The reaction was allowed to stir at room temperature for 1hour. The reaction mixture was diluted with DCM, washed with saturatedaqueous NaHCO₃ solution and brine, dried and concentrated. The resultingresidue was purified by column chromatography (DCM:7N ammonia in MeOH,30:1) to give the free base, which was taken up in DCM and acidifiedwith 2N HCl in ether. Removal of the solvents under reduced pressuregave(5R,7R)-4-(3-(1-(4-chlorophenyl)-2-(isopropylamino)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oltrihydrochloride. LCMS (APCI+) m/z 479, 481 [M+H]+; Rt=2.69 min.

While the invention has been described in conjunction with theenumerated embodiments, it will be understood that they are not intendedto limit the invention to those embodiments. On the contrary, theinvention is intended to cover all alternatives, modifications andequivalents, which may be included within the scope of the presentinvention as defined by the claims. Thus, the foregoing description isconsidered as illustrative only of the principles of the invention.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

What is claimed is:
 1. A method of treating a disease or disordermediated by increased AKT protein kinase activity comprisingadministering to a mammal having said disease or disorder an effectiveamount of a compound of formula I to inhibit activity of an AKT proteinkinase:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:R¹ and R^(1a) are independently selected from hydrogen, methyl, ethyl,—CH═CH₂, —CH₂OH, CF₃, CHF₂ or CH₂F; R² is selected from hydrogen, OH,OCH₃ or F; R^(2a) is selected from hydrogen, methyl or F, or R² andR^(2a) are oxo; L is selected from:

wherein the single wavy line is where L attaches to A and the doublewavy line is where L attaches to the pyrimidine; A is:

X is a direct bond from L to Y, CH₂, O, C═O, NH or C(═O)NH; Y is CH orN; Z is absent, CH₂ or O, wherein L, X, Y, Z and b are selected so thatany nitrogen is not bonded directly to another nitrogen; G is phenyloptionally substituted with one to four R^(a) groups or a 5-6 memberedheteroaryl optionally substituted by a halogen; R³ and R⁴ areindependently selected from hydrogen or methyl; R⁵ and R⁶ areindependently selected from hydrogen or C₁-C₄ alkyl; a is 0 or 1; b is0, 1 or 2; and each R^(a) is independently halogen, C₁-C₆-alkyl,C₃-C₆-cycloalkyl, —O—(C₁-C₆-alkyl), CF₃, —OCF₃, S(C₁-C₆-alkyl), CN,—OCH₂-phenyl, NH₂, —NO₂, —NH—(C₁-C₆-alkyl), —N—(C₁-C₆-alkyl)₂,piperidine, pyrrolidine, CH₂F, CHF₂, —OCH₂F, —OCHF₂, —OH,—SO₂(C₁-C₆-alkyl), C(O)NH₂, C(O)NH(C₁-C₆-alkyl), andC(O)N(C₁-C₆-alkyl)₂; or b is 1, R³ is hydrogen and R⁴ and R⁵ togetherwith the atoms to which they are attached form an optionally substituted5-6 membered heterocyclic ring having one ring nitrogen atom, and R⁶ isselected from the group consisting of H or C₁-C₄ alkyl optionallysubstituted with OH or O(C₁-C₃ alkyl), such that A has the structure:

R^(c) and R^(d) are independently selected from hydrogen and methyl; andc is 1 or 2; or b is 1, Z is CH₂ and R⁵ and Y together with the atoms towhich they are attached form an optionally substituted 6 memberedheterocyclic ring having one ring nitrogen atom, and R⁶ is selected fromthe group consisting of hydrogen or C₁-C₄ alkyl optionally substitutedwith OH or O(C₁-C₃ alkyl), such that A has the structure:


2. The method of claim 1 wherein Formula I is selected from:


3. The method of claim 2, wherein Formula I is selected from:


4. The method of claim 1, wherein L is:


5. The method of claim 1, wherein L is:


6. The method of claim 1, wherein L is:


7. The method of claim 1, wherein L is:


8. The method of claim 1, wherein L is:


9. The method of claim 1, wherein L is:


10. The method of claim 1, wherein L is:


11. The method of claim 1, wherein L is:


12. The method of claim 1, wherein L is:


13. The method of claim 1, wherein X is a direct bond from L to Y, Y isCH and Z is O.
 14. The method of claim 1, wherein X is C(═O)NH, Y is CHand Z is absent.
 15. The method of claim 1, wherein X is a direct bondfrom L to Y, Y is CH and Z is absent.
 16. The method of claim 1, whereinX is NH, Y is CH and Z is absent.
 17. The method of claim 1, wherein Xis C═O, Y is N, Z is absent and b is 1 or
 2. 18. The method of claim 1,wherein X is C═O, Y is CH and Z is absent.
 19. The method of claim 1,wherein R³ is hydrogen.
 20. The method of claim 1, wherein R³ is methyl.21. The method of claim 1, wherein R⁴ is hydrogen.
 22. The method ofclaim 1, wherein R⁴ is methyl.
 23. The method of claim 1, wherein R⁵ ishydrogen.
 24. The method of claim 1, wherein R⁵ is C₁-C₄ alkyl.
 25. Themethod of claim 1, wherein R⁵ is selected from methyl, isopropyl andtert-butyl.
 26. The method of claim 1, wherein R⁶ is hydrogen.
 27. Themethod of claim 1, wherein R⁶ is methyl.
 28. The method of claim 1,wherein b is 1, R³ is hydrogen and R⁴ and R⁵ together with the atoms towhich they are attached form an optionally substituted 5-6 memberedheterocyclic ring having one ring nitrogen atom, such that A has thestructure A8:

wherein c is 1 or 2; R^(c) and R^(d) are independently selected fromhydrogen and methyl; and R⁶ is selected from the group consisting of Hor C₁-C₄ alkyl optionally substituted with OH or O(C₁-C₃ alkyl).
 29. Themethod of claim 28, wherein c is
 1. 30. The method of claim 1, wherein bis 1, Z is CH₂ and R⁵ and Y together with the atoms to which they areattached form an optionally substituted 6 membered heterocyclic ringhaving one ring nitrogen atom, and R⁶ is selected from the groupconsisting of hydrogen or C₁-C₄ alkyl optionally substituted with OH orO(C₁-C₃ alkyl), such that A has the structure A9:


31. The method of claim 1, wherein G is selected from the groupconsisting of 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl and2,4-dichlorophenyl.
 32. The method of claim 1 wherein said compound isselected from the group consisting of:(5R,7R)-4-(4-((S)-(4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol;(5R,7R)-4-(4-((R)-(4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol;N-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide;N-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide;(5R,7R)-4-(4-(4-(4-chlorophenyl)piperidin-4-yl)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol;N-((R)-2-(4-chlorophenyl)-2-(6((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethyl)propan-2-amine;(R)-N-(2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl)propan-2-amine;(5R,7R)-4-(3-(Amino(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol;(5R,7R)-4-(3-(1-(4-Chlorophenyl)-2-(isopropylamino)ethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol;(4-Chlorophenyl)(7((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine;(5R,7R)-4-(3-((R)-1-Amino-2-(4-chlorophenyl)ethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol;(5R,7R)-4-(4-(1-(4-Chlorophenyl)-2-(isopropylamino)ethylamino)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olhydrochloride;(R)-N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide;(R)-N-(2-aminoethyl)-N-(4-trifluoromethylbenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide;(R)-N-(2-aminoethyl)-N-(4-bromolbenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide;(S)-2-(4-bromophenyl)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropiperidin-1(2H)-yl)propan-1-one;(S)-2-(4-bromophenyl)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)propan-1-one;(S)-2-(4-chlorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)ethanone;(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-1-yl)-3 -(isopropylamino)propan- 1 -one; and or (5R,7R)-4-(3-(1-(4-chlorophenyl)-2-(isopropylamino)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol,or a pharmaceutically acceptable salt thereof.
 33. The method of claim 1wherein the disease is cancer.
 34. The method of claim 1 wherein thedisease is a hyperproliferative disease.